NZ331381A - Substituted 4-hydroxy-phenylalcanoic acid derivatives - Google Patents

Substituted 4-hydroxy-phenylalcanoic acid derivatives

Info

Publication number
NZ331381A
NZ331381A NZ331381A NZ33138197A NZ331381A NZ 331381 A NZ331381 A NZ 331381A NZ 331381 A NZ331381 A NZ 331381A NZ 33138197 A NZ33138197 A NZ 33138197A NZ 331381 A NZ331381 A NZ 331381A
Authority
NZ
New Zealand
Prior art keywords
phenyl
methyl
ethoxy
propionic acid
phenylamino
Prior art date
Application number
NZ331381A
Inventor
Timothy Mark Willson
Robert Anthony Mook
Istvan Kaldor
Brad Richard Henke
David Norman Deaton
Jon Loren Collins
Jeffrey Edmond Cobb
Markus Brackeen
Matthew Jude Sharp
John Mark O'callaghan
Greg Alan Erickson
Grady Evan Boswell
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=10789571&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NZ331381(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of NZ331381A publication Critical patent/NZ331381A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The compound has the formula I wherein: A is optionally substituted phenyl, 5 or 6 membered heterocyclic group containing at least one heteroatom selected from O, N or S or a fused bicyclic ring containing a heterocyclic ring as defined above wherein the bicyclic ring is attached to group B via a ring atom of heterocyclic ring; B is alkylene, M-alkylene, alkylene-M, 5 or 6 membered heterocyclic group containing at least one N heteroatom and optionally at least one heteroatom selected from O, N or S or Het-alkylene; M is O, S or NR2; R2 is H or alkyl; Het is 5 or 6 membered heterocyclic group containing at least one N heteroatom and optionally at least one heteroatom selected from O, N or S; Alk is alkylene; R1 is H or alkyl; Z is (alkylene)-optionally substituted phenyl or NR3R4; R3 is H or alkyl; R4 is -Y-CO-T-R5 or -Y(CH(OH))-T-R5 and Y, T and R5 are as defined in the specification. A pharmaceutical composition thereof is useful in the treatment of a PPAR-gamma mediated disease.

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 331 381 <br><br> Intellectual Property Office of New Zealand IP Summary Report <br><br> Page: 1 of 1 Date: 08 June 2000 Time: 11:22:04 (iprip02 2.00.23) <br><br> (51) Classification: <br><br> IPC Edition: IPC <br><br> Status: 70 Accepted <br><br> 331381 <br><br> A61K31/42, <br><br> C07D207/08, <br><br> C07D231/12, <br><br> Version number: 7 IP type: Patent PCT Inward <br><br> Client Ref: P395605 THS/gg <br><br> C07D235/12, <br><br> C07D263/56, <br><br> C07D277/24, <br><br> C07D277/42, <br><br> C07D413/12, <br><br> C07D417/12 <br><br> (86) International Application number: EP97/00916 Date actions completed: <br><br> (87) WO Publication number: 97/31907 Application Accepted 18 May 2000 Elected: Y Next renewal date: 26 February 2001 (22) NZ Filing date: 26 February 1997 <br><br> Date entered National phase: 14 August 1998 <br><br> (30) Priority Data: (31) 96 9604242 (32) 28 February 1996 (33) <br><br> Mook, Robert Anthony Kaldor, Istvan Deaton, David Norman Cobb, Jeffrey Edmond Sharp, Matthew Jude Erickson, Greg Alan Bos well, Qrady Evan O'Callaghan John Mark Brackeen, Markus <br><br> Collins, Jon Loren Henke, Brad Richard Contact: A J PARK, 6th Floor, Huddart Parker Building, 1 Pott Office Square, Wellington, New Zealand <br><br> Primary Examiner: JENNY JEBSON Journal: 1452 <br><br> Office title: Subatltutod 4-hydroxy-phenylalcanolc acid derivatives <br><br> (S4) Applicant title: Subatltutod 4-hydroxy-phenylalc^nolc acid derivatives with agonist activity to PPAR-gamma <br><br> 6B <br><br> (71) Applicant: GLAXO GROUP LIMITED, Glaxo Wellcome <br><br> House, Berkeley Avenue, Greenford, Middlesex UB6 ONN, United Kingdom <br><br> (72) Inventors: Willson, Timothy Mark <br><br> Drawing: <br><br> (0 <br><br> " End of report" <br><br> WO 97/31907 <br><br> PCT7EP97/00916 <br><br> 1 <br><br> substituted 4-hydroxy-phenylalcanoio acid derivatives with agonist activity to ppar-6amma <br><br> The present invention relates to certain novel compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in 5 medicine. More particularly, it relates to compounds which exhibit activation, including agonist activity, to peroxisome proliferator-activated receptor gamma (PPAR-gamma) thereby enabling them to modulate the blood glucose levels in mammals. <br><br> 10 The treatment of Type II or Non-Insulin Dependent Diabetes Mellitus (NIDDM) remains unsatisfactory despite the widespread use of insulin, sulfonylureas (e.g. chlorpropamide, tolbutamide, tolazamide), and biguanides (e.g, phenfcrmin, metformin) as oral hypoglycaemic agents. Treatment of NIDDM usually begins with a combination of diet and exercise, with progression to oral hypoglycaemics (e.g. 15 sulfonylureas) and in more severe cases, insoKrt . Unfortunately the available hypoglycaemics suffer from a wide range of undesirable toxit effects which limits their usefulness in treatment of NIDDM. There is thus a clear needMor the development of novel hypoglycaemic agents which may be less toxic or which suceed where others are ineffective. <br><br> 20 <br><br> In the last decade a class of compounds Known as thiazolidinediones (e.g. U.S. Pat Nos. 5,089,514, 4,342,771, 4,367.234. 4,340,605, 5,306,726) have emerged as effective antidiabetic agents that enhance the insulin sensitivity of target tissues (skeletal muscle, liver, adipose) in animal models of NIDDM and also reduce lipid 25 and insulin levels in these animal models. Recently, the thiazolidinedione troglitazone was shown to have these same beneficial effects in human patients suffering from impaired glucose tolerance, o metabolic condition that precedes the development of NIDDM, as in patients suffering from NIDDM (J. J. Nolan et. al., N. Eng. J. Med. 1188-1193, 331 (1994)). While the mechanism of action is unclear, 30 thiazdidinediones do not cause increases in insulin secretion or in the number or affinity of insulin receptor binding sites, suggesting that thi&amp;zolidinediones amplify post-receptor events in the insulin signaling cascade (J. R. Colca and D. R. Morton, "Antihyperglycemic thiazolidinediones: ciglitazone and its analogs," in New Antidiabetic Dnigs, C. J. Bailey and P. R. Flatt, eds., Smith-Gordon, New York, 255-35 261 (1990)). <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 2 <br><br> PCT/EP97/00916 <br><br> Thiazolidinediones also induce the in vitro adipocyte differentiation of preadipocyte cell lines (A. Hiragun, eL al. J. Cell. Physiol. 124-130, 134 (1988); R. F. Kleitzen, et. al., Mol. Pharmacol. 393-398, 41 (1992)). Treatment of pre-adipocyte cell lines with 5 the thiazolidinedione pioglitazone results in increased expression of the adipocyte-specific r nes aP2 and adipsin as well as the glucose transporter proteins GLUT-1 and GLUT-4, which suggests that the hypoglycaemic effects of thiazolidinediones seen in vivo may be mediated through adipose tissue. <br><br> 10 Recently, an orphan member of the steroid Ahyroid/retinoid receptor superfamily of ligand-activated transcription factors termed Peroxisome Proliferator-Activated Receptor gamma (PPAR-gamma) has been discovered. PPAR-gamma is one of a subfamily of closely related PPARs encoded by independent genes (C. Dreyer, et al.. Cell 879-887, 68 (1992); A Schmidt, et. al.. Mol. Endocrinol. 1834-1641, 6. 15 (1992); Y. Zhu. et. al.. J. Biol. Chem. 26817-26820, 268 (1993); S. A. Kliewer et. al.. Proc. Nat. Acad. Sci. USA 7355-7359, 91, (1994)). Three mammalian PPARs have been isolated and termed PPAR-alpha, PPAR-gamma, and NUC-1. These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE's have been identified in the 20 enhancers of a number of gi nes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endocrin. Met. 291-296, 4 (1993)). It has now been reported that thiazolidinediones are potent and selective activators of PPAR-gamma and bind directly to the PPAR-gamma receptor (J. M. 25 Lehmann et. al., J. Biol Chem. 12953-12956, 270 (1995)), providing evidence that PPAR-gamma is a possible target for the therapeutic actions of the thiazolidinediones. <br><br> We have now discovered a novel group of compounds which bind to and activate 30 the PPAR-gamma receptor. These compounds also show good blood-glucos-lowering activity and are therefore of use in the treatment and/or prophylaxis o hypergtycaemia, dyslipidemia. and are of particular use in the treatment of Type li diabetes. <br><br> Printed from <br><br> Mi.ir.osa <br><br> 3 <br><br> 10 <br><br> These compounds are also indicated to be of use for the treatment ar Hor prophylaxis of other diseases including Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension and cardiovascular disease, especially atherosclerosis. In addition, these compounds are indicated to be useful for the regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. <br><br> Accordingly, the present invention is directed to compounds having the formula (I): <br><br> COjR1 <br><br> Alk C (I) <br><br> wherein <br><br> 15 A is selected from the group consisting of: <br><br> (i) phenyl, wherein said phenyl is optionally substituted by one or more of the following groups; halogen atoms, C^alkyl, Cv3 alkoxy, C,.3 fluoroalkoxy, nitrile, or -NR7R® where R7 and R8 are independently hydrogen or C^alkyl; <br><br> 20 <br><br> (ii) a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and <br><br> (iii) a fused bicyclic ring [ c \ wherein ring C represents a heterocyclic <br><br> 25 group as defined in point (ii) above, which bicyclic ring is attached to group 6 <br><br> via a ring atom of ring C; <br><br> B is selected from the group consisting of; <br><br> 30 (iv) alkylene; <br><br> INTELLECTUAL PROPERTY OFFICE OF N2 <br><br> - 1 MAY 2000 RECEIVED <br><br> WO 97/31907 PCT/EP97/009I6 <br><br> 10 <br><br> (v) -MC^alkylene or C^alkyleneMC^alkylene, wherein M is O, S, or -NR2 wherein R2 represents hydrogen or C,.3alkyl; <br><br> (vi) a 5- or 6- membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further hetei^ jtom selected from oxygen, nitrogen and sulfur and optionally substituted by alkyl; and <br><br> (vii) Het-C^alkylerte, wherein Het represents a heterocyclic group as defined in point (vi) above; <br><br> Alk represents C^alkylene; <br><br> R1 represents hydrogen or alkyl; <br><br> 15 Z is selected from the group consisting of. <br><br> (viii) -(C,.3alkylene) phenyl, which phenyl is optionally substituted by one or more halogen atoms; and <br><br> 20 (ix) -NR'R41, wherein R3 represents hydrogen or C,.3 alkyl, and R4 represents -Y-(C=0)-T-R5 , or -Y-(CH(OH))-T-R5, wherein: <br><br> (a) Y represents a bond, C14 alkylene, C2* alkenylene, C44 cydoalkyiene or cycloatkenyiene, a heterocyclic group as defined in point (vi) above, or <br><br> 25 phenyl optionally substituted by one or more C1.3 alkyl groups and/or one or more halogen atoms; <br><br> (b) T represents a bond, C,.3 alkyleneoxy, -0- or -N(R8)-. wherein R6 represents hydrogen or C1.3 alkyl; <br><br> 30 <br><br> (c) R5 repiesents alkyl, C44 cycloalkyl or cycloalkenyl, phenyl (optionally substituted by one or more of the following groups; halogen atoms, C-i.3 alkyl, C,_3 alkoxy groups, CMplkyleneNR9R10 (where each R9 and R10 is independently hydrogen, alkyl, -SC^C^alkyl, or -COjC^alkyl, - <br><br> 35 S02NHC1.3alkyl), C0.3 alkyleneC02H, C0.3 alkyleneC02C13alkyl. or <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCI/EP97/00916 <br><br> 0CH2C(0)NH2), a 5- or 6- membered heterocyclic group sis defined in point (ii) above, <br><br> a bicylic fused ring wherein ring 0 represents &lt;\ 5- or 6- <br><br> membered heterocyclic group containing at least one hcteroatam selected 5 from oxygen, nitrogen and sulfur and optionally substituted by (=0), which bicyclic ring is attached to T via a ring atom of ring D: or -Ci^alkyieneMR1' M is O, S, or -NR2 wheroin R12 and R11 are independently hydrogen or alkyl; <br><br> 10 or a tautomeric form thereof, and/or a pharmaceutical^ acceptable salt or solvate thereof. <br><br> Those skilled in the art will recognize that stereocenters exist in compounds of Formula (I). Accordingly, the present invention includes all possible stereoisomers 15 and geometric isomers of Formula (I) and includes not only racemic compounds but also the optically active isomers as well. When a compound of Formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final prcduct or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediat» or a 20 starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. Additionally, in situations where tautomers of the compounds of Formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds <br><br> 25 <br><br> It wll also be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of a pharmaceutical^ acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of Formula (I) include conventional salts formed from pharmaceutical^ acceptable 30 inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, male&gt;c, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic. glutamic, benzoic, salicylic, fumaric, toluenesuffonic, <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 6 <br><br> methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their 5 pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,N1-dibenzylethylenediamine, chloroprocaine, choline, tfiethanolamine, ethylenediamine, N-rnethylglucamine and procaine salts. References hereinafter to a compound according to the invention include both compounds of Formula (I) and their 10 pharmaceutically acceptable salts and solvates. <br><br> The terms C^alkyl or alkylene and Chalky I or alkylene as used herein respectively contain 1 to 3 or 1 to 6 carbon atoms and appropriately include straight chained and branched alkyl or alkylene groups, typically methyl, methylene, ethyl and ethylene 15 groups, and straight chained and branched propyl, propylene, butyl and butylene groups. The term C2^alkenyl or alkenylene as used herein contains 2 to 6 carbon atoms and appropriately includes straight chained and branched alkenyl and alkenylene groups, in particular propenylene or the like. <br><br> 20 The term Cv3 alkyleneoxy as used herein denotes -0-C,.3 alkylene-, wherein Ci.3 alkylene is substantially as defined above, e.g. -0-CHr etc. <br><br> The terms C44 cycloalkyl, C44 cycloalkylene, C4^ cycloalkenyl and C4^ cycloalkenylene include cyclic groups containing 4 to 6 carbon atoms, such as 25 cyclopentane, cyclopentylene, cyclohexane, cyclohexylene, cyclohexene and cyclohexenylene. <br><br> The term halogen as used herein includes fluorine, chlorine, bromine and iodine. <br><br> 30 The term 5* or 6-membered heterocyclic group as used herein includes 5- or 6-membered unsubstituted heterocycloalkyl groups and substituted or unsubstituted heteroaryl groups, e.g. substituted or unsubstituted imidazolidinyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, 35 thiazolyl, thiadiazolyl, triazolyl or tetrazolyl. <br><br> Printed from Mimosa <br><br> WO 97/31907 PCT/EP97/00916 <br><br> By substituted heterocyclic group is meant a 5 or 6 membered heteroaryl group substituted by one or more of the following; halogen atoms, alkyl, C,.3 alkoxy groups. Cq_3 alkylene N R9R10 (wf 3re each R9 and R10 is idependently hydrogen, C,. 5 3 alkyl, -S02C1.3 alkyl or CC^C^ alkyl. -S02NHC1.3 alkyl), CM alkylene C02H, CM alkylene C02Cu3 alkyl, -0CH2C(0)NH2, -C,.3 fluoroalkyl, -CN or SC^ alkyl. <br><br> In formula (I) above, in the case where V represents a bond, the nitrogen atom of -NR3R4 is directly linked to -(C=0) or (CH(OH)) of R4, ie. Z represents -N(R3)-(C=0)-10 T-R5 or-N(R3)(CH(OH))-T-R5. Similarly, In the case where T represents a bond, <br><br> (C=0) or (CH(OH)) of R4 is directly linked to R5. ie. Z represents -N(R3)-Y-(C=0)-R6 or -N(R3)-Y-(CH(OH))-R5. It may be the case that both Y and T represent a bond, whereby Z represents -N(R3)-(C=0)-R5 or -N(R3)-(CH(OH))-R5 <br><br> Aptly A represents any of phenyl, heteroaryl (e.g. pyridyl) or c <br><br> 15 ' <br><br> wherein fused ring C represents a 5-membered heteroaryl group containing at least one nitrogen heteroatom and optionally a further heteroatom selected from nitrogen and oxygen (e.g. oxazolyl, imidazolyl). Particularly A represents any of phenyl, <br><br> pyridyl, piperazinyl, or benzoxazolyl, any of which can optionally be substituted by <br><br> 20 one or more C,.3 alkyl, especially phenyl, piperazinyl, or pyridyl. <br><br> B suitably represents any of C^alkylene (e.g. methylene). -NfCh^C^alkylene (e.g. -N(CH3)(CH2)r) or He!-C14 alkylene, wherein Het represents a 5- membered heterocyclic group containing at least one nitrogen heteroatom and optionally at 25 least one further heteroatom selected from oxygen and sulfur (e.g. pyrrolidinyl, oxazolyl and thiazolyl) and aptly substituted by C,.jalkyl. Particularly B represents -N(CH3)(CH2)2. oxazolyl -C^ alkylene, which oxazolyl is optionally substituted by C,.3 alkyl, or thiazolyl which is optionally substituted by C,.3 alkyl. <br><br> 30 Appropriately Alk represents methylene. <br><br> Appropriately R1 represents hydrogen, methyl or ethyl, especially hydrogen. <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> Suitably Z may represent -(Ci.3alkylene) phenyl substituted by one or more halogen atoms, such as optionally substituted benzyl. Preferably Z represents -NR3R4 substantially as hereinbefore described. Generally R3 represents hydrogen. As hereinbefore described, R4 represents -Y-(C=0)-T-R5, or -Y-(CH(OH»-T-R5 5 especially -Y(C=0)-T-R5, and particular groupings represented by R4 include: <br><br> Y represents phenyl (optionally substituted by one or more halogen atoms, or one or more Chalky I e.g. methyl groups), T represents a bond or an oxygen atom, and R5 represents C,_3 alkyl or phenyl (optionally substituted by one or more halogen atoms 10 or one or more C,_3 alkyl groups); <br><br> 15 <br><br> Y represents a heterocyclic group substantially as hereinbefore described (e.g. thienyl), T represents a bond and Rs represents phenyl (optionally substituted by one or more halogen atoms or one or more Ci.3 alkyl groups): <br><br> Y represents C2&lt;,alkenylene- (e.g. propenylene), T represents a bond and Rs represents phenyl (optionally substituted by one or more halogen atoms); <br><br> Y represents C^cycloalken/lene- (e g cyclohexenylene), T represents a bond and 20 R' represents phenyl, <br><br> Y represents phenyl, T represents 3 bond and R* represents a heterocyclic group substantially as hereinbefore described (e g. piperidyl): <br><br> 25 Y represents a bond, T represents a bond and R8 represents a bicyclic ring d substantially as hereinbefore described (e.g. D represents a 6-membered heterocyclic ring, in particular pyranyl substituted by (C*0)); <br><br> Y represents phenyl, T represents a bond and R5 represents C4-ecycloalkyl (e.g. 30 cyclohexyl); <br><br> Y represents phenyl, T represents C,.3 alkyleneoxy (e.g. -0-CH2-) or N(R6)- (e.g. -NH-) and R5 represents phenyl. <br><br> Printed from Mimosa <br><br> s <br><br> Preferably when Z represents NR3R4,R3 represents H and R4 represents Y-(C=0)-T-R5 the said NH and said (C=0) are positioned ortho to each other on Y (which is phenyl), T is a bond or -O-, R5 is alkyl, or phenyl (optionally substituted by one or more: halogen atoms, alkyl, alkoxy groups, Co.3alkyleneNR9R10 where 5 each R9 and R10 is independently hydrogen, alkyl, -SC^C^alkyl, or -C02Cv 3alkyl, - S02NHC.,.3alkyl, C0_3 alkyleneC02H, C0.3 alkyleneC02C1.3alkyl, or -0CH2C(0)NH2). <br><br> Particularly suitably Y represents phenyl, T represents a bond or -O- and R5 10 represents C,.3 alkyl or phenyl e.g. R4 represents <br><br> 15 wherein R13 represents phenyl or OCH3. <br><br> An appropriate subgroup of compounds according to the present invention can be represented by formula (la) <br><br> wherein A and B are substantially as hereinbefore described, and Ar represents phenyl or a 5- or 6- membered heteroaryl group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and salts and solvates thereof. <br><br> 25 Suitably in formula (la), A is selected from phenyl, pyridyl and benzoxazoyl. In particular, A in Formula (la) represents phenyl or pyridyl. Furthermore, B in Formula <br><br> INTELLECTUAL PROPERTY OFFICE OF N.Z. <br><br> - I MAY 2000 RECEIVED <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 10 <br><br> 10 <br><br> (la) is suitably selected from -NRzCi^alkylene substantially as hereinbefore described and Het-C^alkylene optionally substituted by Chalky! substantially as hereinbefore described. In particular, B in Formula (la) represents -N(CH3)(CH2)2- or oxazolyl-Ci^alkylene, which oxazolyl is optionally substituted by Ci.3alkyl, e.g. methyl. <br><br> A particular subgroup of the compounds of formula 1 are compounds of formula (I): wherein; <br><br> A is selected from the group consisting of: <br><br> (i) phenyl optionally substituted by one or more halogen atoms; <br><br> 15 (ii) a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and <br><br> (iii) a fused bicyclic ring c wherein ring C represents a heterocyclic group as defined in point (ii) above, which bicyclic ring is attached to group B 20 via a ring atom of ring C; <br><br> B is selected from the group consisting of: <br><br> (Iv) alkylene; <br><br> (v) -NR3C14alkylene, wherein R2 represents hydrogen or C,.3 alkyl; <br><br> 25 <br><br> (vi) a 5- or 6- membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further heteroatom selected from <br><br> 30 oxygen, nitrogen and sulfur and optionally substituted by C13 alkyl; and <br><br> (vii) Het-C^alkylene, wherein Het represents a heterocyclic group as defined in point (vi) above; <br><br> Printed from Mimosa <br><br> WO 97/31907 PCT/EP97/D09I6 <br><br> 11 <br><br> Alk represents C^alkylene; <br><br> R1 represents hydrogen or C^.3 alkyl; <br><br> 5 Z is selected from the group consisting of; <br><br> (viii) -(C1.3alkylene) phenyl, which phenyl is optionally substituted by one or more halogen atoms; and <br><br> 10 (ix) -NR3R4, wherein R3 represents hydrogen or CV3 alkyl, and R4 represents -Y-(C=0)-T-R5 , or -Y-(CH(OH))-T-R5, wherein: <br><br> (a) Y represents a bond. C14 alkylene, C24 alkenylene, C44 cycloalkylene or cycloalkenylene, a heterocyclic group as defined in point (vi) above, or <br><br> 15 phenyl optionally substituted by one or more C,.3 alkyl groups and'or one or more halogen atoms; <br><br> (b) T represents a bond, alkyteneoxy, -0- or -N(R3)-, wherein R6 represents hydrogen or C,.3 alkyl; <br><br> 20 <br><br> (c) R5 represents Ct^ alkyl, cycloalkyl or cycloalkenyl, phenyl optionally substituted by one or more halogen atoms or one or more C,.3 alkyl groups, a 5- or 6- membered heterocyclic group as defined in point (ii) above. <br><br> or a bicylic fused ring d wherein ring D represents a 5- or 6- <br><br> 25 membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by (=0). which bicyclic ring is attached to T via a ring atom of ring 0; <br><br> or a tautomeric form thereof, and/or a pharmaceutically acceptable salt or solvate 30 thereof <br><br> Particular compounds according to the present invention include. <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 12 <br><br> 3-(4-Benzyloxy-phenyl)-2(S)-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid dicyclohexylamine salt <br><br> 3-(4-Benzyloxy-pheny1)-2(S)-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid methyl ester <br><br> 5 2(S)-(2-Benzoyl-cyclohex-1 -enylamino)-3-(4-benzy!oxy-phenyl)-propionic acid dicyclohexylamine salt <br><br> 2-{2-benzoylphenylamino)-3-(4-benzyloxyphenyl) propanoic acid <br><br> 3-&lt;4-Benzyloxy-phenyl)-2-(2-ben2yloxy-phenylamino)-propionic acid methyl ester 3-(4-Benzyloxy-phenyl)-2-(phenylcarbamoyl-phenylamino)-propionic acid methyl <br><br> 10 ester <br><br> 3-&lt;4-Benzyloxy-phenyl)-2-[2-(piperidine-1-carbonyl)-phenylamino)-propionic acid methyl ester <br><br> 2-(3-Benzoyl-thiophen-2-yl-amino)-3-(4-benzyk&gt;xy-phenyl)-propionic acid 2-(2-Benzoyl-thiophen-3-yl-amino)-3-(4-benzyloxy-phenyl)-propionic acid 15 3-(4-Benzyloxy-phenyl)-2(S)-[(4-oxo-4H-chromene-3-carbonyl)-amino]-propionic acid methyl ester. <br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-20 propionic acid <br><br> 2-(2-Benzoyl-phenylamino)-3-{4-|2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid ethyl ester <br><br> 2-(1-Methyl-3-oxo-3-phenyl-propenylamino)-3{4-[2-{methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid dicyclohexylamine salt <br><br> 25 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-phenylamino)-propionic acid <br><br> 3-{4-{2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-ber»zoyl-phenylamino)-propionic acid <br><br> 3-{4-[2-(Benzoxazol-2yl-methyl-amino)-ethoxy]-phenyl}-2(S)-(1-methyl-3-oxo-3-30 phenyl propenylamino)-propionic acid dicyclohexylamine salt <br><br> 3-{4-{2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2(S)-[3-(3-iodo-phenyl)-1-methyl-3-oxo-propenylamino]-propionic acid dicyclohexylamine salt 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-4-methyl-phenylamino)-propionic acid <br><br> Printed from Mimosa <br><br> &amp; <br><br> cu w <br><br> 6 <br><br> 0. <br><br> s o * <br><br> 2 <br><br> 0 <br><br> 3 <br><br> x ? <br><br> &gt;» c <br><br> 0) <br><br> c. <br><br> CL <br><br> J. <br><br> r <br><br> £ © <br><br> E <br><br> &lt;N <br><br> 1 <br><br> &gt;« £ » <br><br> E •o <br><br> I <br><br> cm co i <br><br> o c <br><br> E <br><br> n <br><br> &gt;» <br><br> c « <br><br> 5* g <br><br> © <br><br> a * <br><br> &lt;N <br><br> 4 <br><br> n m <br><br> x <br><br> 9 <br><br> &gt;. <br><br> c 01 <br><br> c. o. <br><br> o <br><br> 3 <br><br> J <br><br> » <br><br> cm &gt;» <br><br> ■o 0 <br><br> CB <br><br> U <br><br> c o <br><br> Q. <br><br> S a si. &gt;. <br><br> c © <br><br> c. a. <br><br> © <br><br> E ai i <br><br> cm <br><br> CO <br><br> i o" c <br><br> E <br><br> (0 <br><br> &gt;. <br><br> c a&gt; <br><br> C. <br><br> a <br><br> &gt;&gt; <br><br> 0 <br><br> n <br><br> C % <br><br> 1 <br><br> cm <br><br> TJ U &lt;0 o 'c o a. o <br><br> X. &gt;. <br><br> o <br><br> N <br><br> a <br><br> X <br><br> o <br><br> &gt;N • <br><br> CM <br><br> i c <br><br> 4? <br><br> j= <br><br> a&gt; <br><br> E * <br><br> «o <br><br> &gt;. <br><br> ■C © <br><br> E uS <br><br> I <br><br> cm n o <br><br> E <br><br> m <br><br> &gt;&gt; <br><br> c a&gt; <br><br> a a <br><br> &gt;. c 0 <br><br> T <br><br> co a cm o £ <br><br> CO <br><br> cm <br><br> I <br><br> c © <br><br> -Q cm <br><br> X <br><br> w s? <br><br> 0 £ <br><br> 1 &gt;. <br><br> th <br><br> I <br><br> o <br><br> N <br><br> a <br><br> &gt;. <br><br> 9-x <br><br> &gt;. <br><br> c © <br><br> ■S» ii- Q. <br><br> cm <br><br> 2 u a o c o a. o <br><br> © <br><br> E uS <br><br> cm <br><br> « <br><br> o" <br><br> c <br><br> E a c 5 <br><br> ® m £ « a. o <br><br> U Cb <br><br> ^ &gt;» <br><br> &gt;s c © <br><br> JZ <br><br> a r <br><br> cm © <br><br> o .2 <br><br> n a c o e» t <br><br> ' c co ® <br><br> ?J Q. <br><br> iO <br><br> m o <br><br> cm m cm o co <br><br> 14 <br><br> 33 138 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-piperidin-1-yl-oxazol-4-yl)-ethoxy]-phe;nyl}-propionic acid <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-morpholin-4-yl-thiazoi-4-yl)-ethoxy]-phenyl)-propionic acid <br><br> 2(S)-{2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(4-pyridyl)-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> 2(S)-(2-benzoyl-phenylamino}-3-{4-[2-(2-dimethyfamino-5-methyMhiazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> 2(S)-(2-ben2oyl-phenylamino)-3-{4-[2-(5-methyl-2-(5-methyl-isoxazol-3-yl)-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-methyl-2-(4-methyl[1,2,3]thiadiazol-5-yl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid <br><br> 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-methyl-2-(4-methyl-piperazin-1-yl)- thiazol-4-yl]-ethoxy}-phenyl)-propionic acid <br><br> 2-(1-Carboxy-2-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-€thoxy]-phenyl}-€thylarnino)-benzoic acid methyl ester <br><br> 2-( 1 -Carboxy-2-(4-[2-(4-clhorophenylsulfany l)-ethoxy]-phenyl}-ethylamino)- benzoic acid methyl ester <br><br> 3-{4-{2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]'phenyl}-2-(2-cyclopentanecarbonyl- <br><br> phenylamino)-propionic acid <br><br> INTELLECTUAL PROPERTY OFFICE OF N1. <br><br> 2 8 APR 2000 <br><br> RECEIVED <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 15 <br><br> 20 <br><br> 15 <br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-cyc!ohexanecarbonyl-5-fluoro-phenylamino)-propionic acid <br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(4-cyclohexanecarbonyl- <br><br> 2-methyl-2 H-pyrazol-3-ylamino)-propionic acid <br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxyJ-phenyl}-2-(3-benzoyl-thlophene-2-y!amino)-propionic acid <br><br> 2-(2-Cyclohexanecarbonyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> 2-(2-CydohexanecarbonyUphenylamino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> 3-(4-(1-Benzoxazol-2-yi-pyrrolidin-3-ytoxy)-phenyl]-2-(2-l&gt;enzoyl-phenylaminc)-propionic add <br><br> 3-{4-[2-(£ Methyl-2-phenyl-oxazol-4-yl)-ethoxy}-phenyl}-2(SH2-(pyridine-4-carbonyl)-phei yta'ninoj-propionic acid <br><br> 3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2(S)-[2-(pyridineN-oxide-4-carbonyl)-phr»nylamino)-propionic add {4[2-(5-Methyl-2-phenyl-oxazol-4-yl)-sthoxyl-phenyl&gt;-2(S)-[2-(pyridine~3-carbonyl&gt;-inylaminoj-propionic acid 3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2(S)-|2-(pyridine-N-oxide-3-carbonyl)-phenylamino]-propionic add <br><br> 2S-(2-benzoyl-phenylamino)-3-{4-|2-(5-rr~A^y|-3-phenyJ-pyrazol-1-yl)-ethoxyJ-phenyl}-propionic acid <br><br> 2S-(2-benzoyt-phenylamino)-3-I4-&lt;1-pyridin-2-yl-pyrTolidin-2S-yf-methoxy)-phenyl]-propionic acid <br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(1-methyl-4-phenyHH-imidazo!-2-yl)-ethoxy]-phenyl)-propk&gt;nic acid <br><br> 2S-(2-benzoyl-pher»ylamino)-3-{4-[2-(3-furan-2-yl-5-methyl-pyrazo!-1-yl)-ethoxy]-phenyt)-propionic acid <br><br> Prir.ted from Mimosa <br><br> 33 1381 <br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-3-phenyl-[1,2,4]triazol-1-yl)-ethoxy]-phenyl}-propionic acid <br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(3-methoxymethyl- 5-methyl-2-phenyl-3H-imidazol~4-yl)-ethoxy]-phenyl}-propionic acid <br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyi-3H-imidazol-4-yl)-ethoxy]-phenyl)-propionic acid hydrochloride salt <br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(3-methyl-thien-2-yl)-oxazol-4-yl)-10 ethoxy]-phenyl)-propionic acid <br><br> 2(S)-(2-{4-[2-(5-chloro-2-pyridylsulfanyl)-ethoxy]-phenyl}-1-methoxycarbonyl-ethylamino)-benzoic acid <br><br> 2(S)-(2-{4-[2-(N-ethyl-2-methyl-toluidino)-ethoxy]-phenyl}-1-methoxycarbonyl -ethylamino)-benzoic acid 15 3-[4- ^3-Benzoxazol-2-yl-thiazolidin-4(R)-ylmethoxy)-phenyl]-2(S)-(2-benzoyl-phenylamino)-propionic acid <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-{2-(4-trifluoromethyl-benzoyl)-phenylamino-propionic acid <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(2-thiophenecarbonyl)-phenylamino-propionic acid <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(3-thiophenecarbonyl)-phenylamino-propionic acid <br><br> 20 <br><br> 25 <br><br> INTLLLECl UAL ,r-i:0rhRTY Of-Hcl" IF N.Z. I <br><br> 2 8 APR 2000 RECEIVED <br><br> 331381 <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(3-methoxy-benzoyl)-phenylamino-propionic acid <br><br> 3-{4-[2-(benzoxazol-2-yl-methyt-amino)-ethoxy]-phenyl)-2-[2-(2-methoxy-benzoyl)-phenylamino-propionic acid <br><br> 3_[4_[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl)-2-[2-(3-methyl-benzoyl)-phenylamino-propionic acid <br><br> 2-[2-(4-dimethylaminomethyl-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid hydrochloride <br><br> 2-[2-(4-aminomethyl-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-y!)-ethoxy]-phenyl}-propionic acid hydrochloride <br><br> 3-{4-{2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(2,6-dimethylbenzoyi)-phenylamino-propionic acid <br><br> 3-(2-{1-carboxy-2-[4-(2-{5-methyl-2-phenyl-oxazoM-yl}-ethoxy)-phenyl]-ethylamino}-benzoyl benzoic acid <br><br> 2-[2-(3-aminomethyl-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid hydrochloride <br><br> 2-[2-(3-dimethylaminomethyl-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid hydrochloride <br><br> 2(S)-(1-carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]"phenyl}-ethylamino)-benzoic acid methyl ester <br><br> 2(S)-(1-carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-y,)-ethoxy]-phenyl}-ethylamino)-benzoic acid 2-aminoethyl amide hydrochloride <br><br> 2-(1-carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethylamino)- <br><br> benzoic acid methyl amide <br><br> INT.LLL'J i J/-.;. ' • ... rrfv ] <br><br> OF N Z " I <br><br> !S <br><br> 2 8 APR 2000 <br><br> RECEIVED <br><br> 33 1381 <br><br> 18 <br><br> 3-(4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-[2-(4-propylsu!famoyl-benzoyl)-phenylamino]-propionic acid <br><br> 2-[2-(3-methanesulfonylamino-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> 2-[2-(3-methoxycarbonylamino-benzoyl)-phenylamino]-3-{4-[2-(5-rnethyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-prop!onic acid <br><br> 2-[2-(3-carbanoylmethoxy-benzoyl)-phenylamino]-3-{4-[2-(5-methy!-2-phenyl-oxazo!- <br><br> 4-yl)-ethoxy]-phenyl)-propionic acid <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-pyridin-4-yl-oxazol-4-yl)-ethoxy]-phenyiy-propjonic acid <br><br> 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-methyl-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid hydrochloride <br><br> 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-methyl-2-(4-tert-butoxycarbonyl-piperazin-1-yl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyI-2-piperazin-1-yl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> (S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-methyl-2-(4-methylsiilfonyl-piperazin-1-yl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid <br><br> 2(S)-(1-carboxy-2-{4-[2-(4-dimethylamino-phenyl)-ethoxy]-phenyl}-ethylamino)-benzoic acid methyl ester <br><br> 2(S)-[1-methoxycarbonyl-2-(4-{2-[5-methyl-2-(4-methyl-pipei,azin-1-yl)-thiazol-4-yl]-ethoxy}-phenyl)-sthylamino}-benzoic acid <br><br> C N.Z. <br><br> 2 8 APR 2000 RECEIVED <br><br> 331381 <br><br> 2(S)-(1-carboxy-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethylamino)-ben2oic acid methyl ester <br><br> 2(S)-(1-carboxy-2-{4-[2-(4-trifluoromethoxy-phenyl)-ethoxy}-phenyl}-ethylamino)-benzoic acid methyl ester <br><br> 3-{4-[2-(Benzoxazol-2-y!-methylamino)-ethoxy]-phenyl}-3-{4-benzoyf-thienylamino)-propionic acid <br><br> 3-(4-[2-(Benzoxazol-2-yl-methylamino)-ethoxy]-phenyl}-2-(2-(4-methoxy-benzoyi)-phenylamino)-propionic acid <br><br> 3-{4-[2-(Benzoxazol-2-yl-methylamino)-ethoxy]-phenyl}-2-(2-(4-methyl-benzoyl)-phenylamino)-propionic acid <br><br> 3-{4-[2-(Benzoxazol-2-yl-methylamino)-ethoxy]-phenyl}-2-(2-(2 -methyl-benzoyl)-phenylamino)-propionic acid <br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(4-ch{oro-phenyl)-ethoxy]-phenyl}-propionic acid 2-(2-Benzcyl-phenylamino)-3-{4-[2-(4-metbyl-thiazol-5-yl)-ethoxy]-phenyl}-propionic acid <br><br> 2-(2-Benzoyt-phenylamino)-3-{4-2[-(4-chloro-phenylsulfanyl)ethaxy]- phenyl}-propionic acid <br><br> 2-(2-Benzoyl-phenylamino)-3-[4-(4-isopropyl-benzyloxy)-phenyl]-propionic acid 2-(2-Benzoyl-phenylamino)-3-[4-(4-chloro-benzyloxy)-phenylJ-propionic acid 2-(2-Benzoyl-phenylamino)-3-{4-[3-(4-methoxy-phenyl)-propoxy]-phenyl}-propionic acid <br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(4-dimethylamino-phenyl)-ethoxyJ-phenyl}-propionic acid <br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(4-bromo-phenoxy)-ethoxy]-phenyl}-propionic acid <br><br> INTELLECTUAL PROPERTY OFFICE OF N.Z. <br><br> 2 8 APR 2000 RECEIVED <br><br> -53 138 1 <br><br> 10 <br><br> 2-(2-Benzoyl-phenylamino)-3-(-4-{2-[3-(6-methyl-pyridin-2-yl)-propoxy]-ethoxyl}-phenyl)-propionic acid <br><br> 2-(2-3enzoyl-phenylamino)-3-[4-(2-pyridin-3-yl-ethoxy]-phenyl]-propionic acid 2-(2-Benzoyl-phenylamino)-3-{4-[2-(3-methyl-6-oxo-6H-pyridazin-1-yl)-ethoxy]-pheny(}-propionic acid <br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(4-trifluoromethoxy-phenyl)- ethoxy]-phenyl}-propionic acid <br><br> 2-(2-Benzoyl-phenylamino)-3-(4-[2-(3-cyano-phenoxy)-ethoxy]-phenyl}-propionic acid <br><br> 2-(2-Bsnzoyl-phenylamino)-3-[4-[2-(6-methoxy-pyridin-2-ylsulfanyl)-ethoxy]-phenyl}-propionic acid <br><br> A particular subgroup by compounds according to the present invention include: <br><br> 2(S)-(1-carboxy-2-{4-{2T(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethylamino)-benzoic acid methyl ester 15 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2(S)-(2-benzoyl-phenylamino)-propionic acid; <br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-cyclohexanecarbonyl-pheny!amino)-propionic acid, <br><br> 3-{4-[2-Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-thiophen-3-ylamino)-propionic acid. <br><br> 2(S)-[1-methoxycarbonyl-2-(4-{2-[5-methyl-2-(4-methyl-piperazin-1-yl)-thiazoM-yl]-ethoxy&gt;-phenyl)-ethylamino]-berizoic acid <br><br> 2(S)-(2-benzoyl-phenyiamino)-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl&gt;-propionic acid; <br><br> 2(S)-(2-Benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenylj-propionic acid; <br><br> 20 <br><br> 25 <br><br> and pharmaceutically acceptable salts and solvates thereof. <br><br> INTELLECTUAL PROPERTY OFFICE OF N.Z. <br><br> 2 8 APR 2000 <br><br> RECEIVED <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 21 <br><br> The invention further provides a compound of Formula (I), or (la), or a pharmaceutically acceptable salt or solvate thereof, for use in therapy, and in particular, in human medicine. <br><br> 5 According to another aspect, the present invention provides the use of a compound of Formula (I), or (la), or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of conditions where modification of the effects of PPAR-gamma is of therapeutic benefit. <br><br> 10 According to a further aspect of the present invention, there is provided herein a method for the treatment of a mammal, including man, in particular in the treatment conditions where modification of the effects of PPAR-gamma is of therapeutic benefit, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or (la), or a pharmaceutically 15 acceptable salt or solvate thereof. <br><br> It will be appreciated by those skilled in the ~rt that reference herein to treatment extends to prophylsxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the 20 invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02 - 5000 mg per day, e.g., 1-1500 mg per day. The desired dose may conveniently be presented 25 in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. <br><br> While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as 30 a pharmaceutical formulation. Accordingly, the present invention further provides for a pharmaceutical formulation comprising a compound of Formula (I), or (la), or a pharmaceutically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense of 35 being compatible with the other ingredients of the formulation and not deleterious to <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/0C916 <br><br> 22 <br><br> the recipient thereof. There is further provided by the present invention a process of preparing a pharmaceutical formulation comprising a compound of formula (I), or (la), which process comprises admixing a compound of formula (I), or (la), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically 5 acceptable carriers therefor, and optionally other therapeutic and/or prophylactic ingredients. <br><br> Formulations of the present invention include those especially formulated for oral, buccal, parenteral, transdermal, inhalation, intranasal, transmucosal, implant or 10 rectal administration, however, oral administration is preferred. For buccal administration, the formulation may take the form of tablets or lozenges formulated in conventional manner. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, 15 lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium iauryl sulfate. The tablets may be coated according to methods well-known in the art. <br><br> 20 <br><br> Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable 25 vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as 30 almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p tydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 23 <br><br> PCT/EP97/00916 <br><br> Additionally, formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or 5 dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use. <br><br> The formulations according to the invention may also be formulated as a depot preparaton. Such long acting formulations may be administered by implantation (for <br><br> 10 example, subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil. for example), ion exchange resins or as sparingly soluble derivatives as a sparingly soluble salt, for example. <br><br> 15 <br><br> The formulations according to the invention may contain between 0.1 - 99% of the active ingredient, conveniently from 30 - 95% for tablets and capsules and 3 • 50% for liquid preparations. <br><br> 20 There is further provided by the present invention processes for the preparation of compounds of formula (I). Unless otherwise indicated, A, B, Alk, R' and Z (and the further substituents represented thereby) are substantially as hereinbefore described. <br><br> 25 According to a general process (A), a compound of formula (I) may be prepared from a compound of formula (II) <br><br> ^ ^ AIL ' <br><br> ** \ (it) <br><br> H°—^ z <br><br> 30 either directly, or indirectly, via a single or muttistep reaction by reacting with a compound of formula A-B-X wherein X is a leaving group or a hydroxy! group, and B re[resents a group comprising alkylene, B being such that X is bonded directly to a C,^ alkylene. <br><br> Printed from Mimosa <br><br> 24 <br><br> J <br><br> Suitable reaction conditions are described below and in the accompanying Examples. See also, for example, Chung et al.. Selective Functionalization of (S)-Tyrosine, Tetrahedton, 49(26), pp. 5767-5776. (1993), Solar et al., Selective O-5 Alkylation of Tyrosine, Journal of Organic Chemistry, 31, pp 1996-1997 (1966), O. Mitsunobu, Synthesis, p 1 (1981), and D.L. Hughes, Org. React. Vol. 42, p 335 (1992). <br><br> For example, A is preferably phenyl, pyridyl, benzoxazolyl or piperazinyl, any of 10 which may optionally be substituted by one or more C1.3alkyl groups. More preferably, A represents phenyl, pyridyl, benzoxazolyl (piperazinyl). <br><br> B is preferably Het-C^ alkylene as descibed hereinbefore and Z is preferably -NH-Y-(C=0)-T-R5 wherein Y is phenyl, optionally substituted by one or more C1.3alkyl 15 groups and^or one or more halogen atoms; T is a bond or -O- and RJ&gt; represents <br><br> C^alkyl or phenyl (optionally substituted by one or more halogen atoms, C,.3 alkyl, CV3 alkoxy groups, Co.3alkyleneNR9R10 where each R9 and R10 is independently hydrogen, C|.3 alkyl, -S02C,.3alkyl, or C02C,.3alkyl, S02NHC,.3alkyl, C0.3 alkyleneC02H, Co.3alkyleneC02C,.3alkyl, or -0CH2C(0)NH2). <br><br> More preferably X represents a halide group or an alkyl- or arlysulfonoxyl group and R1 represents hydrogen. Even more preferably, the compounds of formulae ABX and formula (II) are; <br><br> wherein OMs is a mesylate leaving group and R13 represents a phenyl or OCH3 group. <br><br> 20 <br><br> 25 <br><br> and intellectual property office of n2. <br><br> 2 7 MAR 2000 <br><br> RECEIVED <br><br> 25 <br><br> J5 15 <br><br> f <br><br> In compounds of formula (II) wherein R1 represents a C^alkyl group, preferably methyl, and X a hydroxyl group the reaction between ABX and the compound of formula (U) comprises a Mitsunobu reaction followed by hydrolysis of the alkyl ester group to the corresponding acid without isolating the ester. Preferably the Mitsunobu reaction mixture comprises toluene. <br><br> More preferably the compounds of formulae ABX and (II) are then the compound of formula (II) is prepared by first preparing a compound of formula (II) wherein Z is wherein R13 is a phenyl or OCH3 group. <br><br> When Z represents the following compound intellectual property office of n2. <br><br> 27 MAR 2000 <br><br> RECEIVED <br><br> 26 <br><br> followed by a dehydrogenation with a dehydrogenation catalyst in the presence of a hydrogen acceptor. Preferably this hydrogen acceptor is an aromatic nitro compound. <br><br> 5 A compound of formula (I) may be prepared by reaction with A-B-X, B being such that X is bonded directly to a Ci^alkylene as described above and wherein X is a hydroxyl group or a suitable leaving group such bs a halogen or an alkyl- or arylsulfonyloxy group (e.g. mesylate). <br><br> 10 Alternatively, in the case wherein B represents -NF^Cuealkylene, a compound of formula (I) may be prepared from a compound of formula (II) via a protected intermediate which can appropriately be represented by formula (III) <br><br> coyr1 <br><br> | |^p A* &lt; (in) <br><br> CH, N — C,^ alkylene o —Z <br><br> 15 <br><br> wherein P represents a protecting group, such as an alkoxycarbonyl e.g. t-butoxycarbonyl or the like, using techniques as hereinafter described in the accompanying Examples and representing protection and deprotection reactions known in the art e.g. as described in T.W. Green &amp; P.G.M. Wuts (1991), Protecting 20 Groups in Organic Chemistry, John Wiley &amp; Sons. <br><br> A compound of formula (II) can, for example, be prepared from a compound of formula (IV) <br><br> suitably by reaction with a diketone e.g. 2-benzoyl-cyciohexanone, appropriately in the presence of a metal catalyst e.g. palladium. Preferably, R1 is alkyl, and the diketone is first reacted with the amine followed by dehydrogenation in the presence 30 of a metal catalyst and a hydrogen acceptor. Preferable hydrogen acceptors are aromatic nitro compounds that are easily reduced, e.g., p-nitrotoluene. If it is intellectual property office of N.Z. <br><br> ' t MAY 2000 RECEIV/Pn <br><br> 27 <br><br> desired for R1 to be hydrogen, the compound where R1 is alkyl can be hydrolyzed, for example, in base in a solvent mixture of water and a polar-aprotic solvent. A compound of formula (IV) is commercially available or may be prepared as described in J. Med. Chem 1978, 21(5), 430-7. <br><br> 5 <br><br> According to a further general process (B), a compound of formula (I) may be prepared from a compound of formula (V) <br><br> co2r' <br><br> Alk—( M <br><br> a —b—o—n2 <br><br> • 10 <br><br> suitably by reaction with NR3R4H. For example, the reaction may be carried out suitably by reflux in the presence of a metal catalyst e.g. a rhodium catalyst (rhodium acetate dimer), and appropriately a hydrocarbon solvent e.g. toluene or the like. It will be appreciated that process (B) yields compounds of formula (I) wherein Z 15 represents-NR3R4. <br><br> A compound of formula (V) may be prepared by diazotization of a compound of formula (VI) <br><br> Appropriately the diazotization reaction is carried out by reflux in the presence of a nitrite e.g. isoamyl nitrite. <br><br> 25 Compounds of formula (VI) may be commercially available e.g. O-benzyl-tyrosine methyl ester. Alternatively compounds of formula (VI) may be prepared from known starting materials e.g. a benzoxazole halide and an aminoalcohol as hereinafter described in the accompanying examples. <br><br> 30 A compound of formula (I) may however be prepared directly from a compound of formula (VI) via a general process (C). For example, a compound of formula (VI) <br><br> intellectual property office of n.z. <br><br> - 1 MAY 2000 <br><br> 28 <br><br> 10 <br><br> may be reacted with a diketone of general formula CH3-(CH2)n-(C=0)-CH2-(C=0)-T-R5, where n is an integer selected from 0 to 3, so as to yield a compound of formula (I) wherein Z represents -NH-C2^a'kenylene-(C=0)-T-R5. In a further embodiment, a compound of formula (VI) may be acylated by reaction with R5-(C=0)-X, where X is a suitable leaving group substantially as hereinbefore described, suitably in the presence of a base e.g. a tertiary amine, such as triethylamine or the like. <br><br> According to a further process (D), a compound of formula (•) may be prepared from a compound of formula (VII) <br><br> Alk— CH,— C02R' (VII) <br><br> A— B- <br><br> by reaction with a strong base, suitably an alkali metal amide, followed by reaction with a compound of formula Z-X, where X is a suitable leaving group as hereinbefore 15 described. In particular, process (D) is employed in the preparation of compounds of formula (I) wherein Z represents-(C1.3 alkylene)phenyl substantially as hereinbefore described. Suitably, the reaction is carried out in the presence of an ether solvent, e.g. tetrahydrofuran with stirring for several hours. <br><br> 20 Appropriately, a compound of formula 'Vii) may be prepared from compounds of formulae (VIII) and (IX); <br><br> A— B— p <br><br> (VIII) (IX) <br><br> 25 wherein P may be a suitable protecting group substantially as hereinbefore described. Compounds of formula (IX) are commercially available. Compounds of formula (VIII) may be prepared from known starting materials, using techniques, for example, as referred to above starting from a benzoxazole halide and an aminoalcohol. <br><br> 30 <br><br> intellectual property office of n.z. <br><br> - 1 MAY 2000 RECEIVED <br><br> 29 <br><br> 5 <br><br> 15 <br><br> 20 <br><br> According to a further general process (E). a compound of formula (I) may be prepared by cyclisation of a compound of formula (X) <br><br> to yield a compound of formula (I) wherein A represents a bicyclic ring c \ C being a 5- or 6-membered heterocyclic ring containing two nitrogen heteroatoms, the cyclisation conveniently being earned out in an acidic 10 environment. <br><br> Suitably a compound of formula (X) may be prepared from a compound of formula (XI) <br><br> (xi) <br><br> x-b-o ^ " <br><br> by reaction with 1,2-phenylene diamine, suitably in the presence of an alkali metal carbonate e.g. potassium carbonate or the like. X is a leaving group substantially as hereinbefore described, in particular a mesylate group. <br><br> A compound of formula (XI) can be prepared from a compound of formula (XII) <br><br> (XII) <br><br> suitably by reaction with, for example, an alkyl or aryl sulfonyl halide, e.g. 25 methanesulfonylchloride, appropriately in the presence of an ether solvent e.g. tetrahydrofuran, and a tertiary amine e.g. triethylamine. <br><br> Tntellectual property omut i of n2. <br><br> - \ MAY 2000 RECEIVED <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 30 <br><br> A compound of formula (XII) may appropriately be prepared from a compound of formula (II) substantially as hereinbefore described, e.g. by reaction with an alkylene carbonate in the presence of an alkali metal carbonate e.g. potassium carbonate. <br><br> 5 According to a further aspect of the present invention a compound of formula (I) can be converted to another compound of formula (I). A particular interconversion reaction involves conversion of a compound of formula (I) wherein R1 represents Ci_ 3alkyl, to a compound of formula (I) wherein R1 represents hydrogen, suitably employing hydrolytic techniques e.g. an alkali metal hydroxide, in the presence of an 10 ether solvent e.g. tetrahydrofuran and an alcoholic solvent e.g. methanol or the like. <br><br> it will therefore be appreciated by persons skilled in the art that compounds which fall within general formula (I), may in some instances, be hereinafter described in the intermediate section, as they are useful for the preparation of other compounds of 15 formula (I). <br><br> For any of the general processes and schemes described above, it may be necessary and/or desirable to protect sensitive or reactive groups . Protecting groups are employed according to standard methods of organic synthesis (T. W. 20 Green and P. 6. M. Wuts (1991) Protecting Groups in Organic Synthesis. John Wiley &amp; Sons). These groups are removed at a convenient stage of synthesis using methods known from the art. Thus, for example, amino groups may be protected by a group selected from aralkyl (e.g. benzyl), acyl, or sulfonyl, e.g. allylsulfonyl, tert-butoxycarbonyl, phthalimide, or tosyl; subsequent removal of the protecting group 25 being effected when desired by hydrolysis or hydrogenolysis as appropriate using standard conditions. Thus, for example, tert-butoxycarbonyl groups may be removed by hydrolysis under acidic conditions. Hydroxyl and carboxyl groups may be protected using any conventional hydroxyl or carboxyl protecting group. Examples of suitable hydroxyl and carboxyl protecting groups include groups 30 selected from alkyl. e.g. methyl, tert-butyt, or methoxymethyl, aralkyl, e.g. benzyl, diphenylmethyl, or triphenylmethyl, heterocyclic groups such as tetrahydropyranyl, acyl. e.g. acetyl or benzoyl, and silyl groups such as trialkylsilyl, e.g. tert-butytdimethylsilyl. The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl, and heterocyclic groups may be 35 removed by hydrolysis under acidic or basic conditions. Aralkyl groups such as <br><br> Printed frem Mimosa <br><br> WO 97/31907 <br><br> 31 <br><br> PCT/EP97/00916 <br><br> triphenylmethyl may similiarly be removed by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved by hydrogenolysis in the presence of a Noble metal catalyst such as paliadium-on-charcoal. Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-5 butylammonium fluoride. <br><br> Many of the above reactions and synthetic routes can be done on solid support. For example, R1 in Formula (II) can represent a suitable solid phase support, for example, R1 can be a 2-chlorotritylchloride polystyrene resin. After performing the 10 appropriate reactions, the desired compound of Formula (I) can be isolated by cleavage from the soid phase support. <br><br> The following examples are set forth to illustrate the synthesis of some particular compounds of the present invention and to further exemplify particular applications 15 of genera! processes described above. Accordingly, the following Example section is in no way intended to limit the scope of the invention contemplated herein. <br><br> As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific titerature, for 20 example, the Journal of the American Chemical Society. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); (microliters); psi (pounds per square inch); M (molar); mM (millimolar); 25 i. v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); RT or rt (room temperature); min (minutes); h (hours); mp. (melting point); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); t, (retention time); RP (reverse phase); MeOH (methanol); TFA (trifluoroacetir acid); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); EtOAc (ethyl acetate); DCM 30 (dichloromethane) ; DMF (dimethylformamide); Et3N (triethylemine); 1,1-carbonyldiimidazole (CDI); isobutylchloroformate (iBuCF); N-hydroxysuccinimide (HOSu); N-hydroxybenztriazole (HOBT); diethyl azodicaboxylate (DEAD); di-tert-butyl dicarbonate ((B0C2)0); ethytcarbodiimide hydrochloride (EDC); bis(2-oxo-3-oxazolidinyl) phosphinic chloride (BOP); tert-butyloxycarbonyl (BOC); 35 dicyclohexylcarbodiimide (DCC); benzyloxycarbonyl (Cbz); NaHC03 (saturated <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/009I6 <br><br> 10 <br><br> 32 <br><br> aqueous sodium bicarbonate). All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCI. Unless otherwise indicated, all temperatures are expressed in 0 C (degrees Centigrade). All reactions conducted at room temperature unless otherwise noted. <br><br> The 1HNMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, or a Varian Unity-400 instrument. Chemical shifts are expressed in parts per million (ppm, 5 units). Coupling constants are in units of hertz (Hz). Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, muitiplet; br, broad. <br><br> Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA, JOEL SX-102 or a SCIEX-APIiii spectrometers. All mass spectra were taken in the positive ion mode under electrospray ionization (ES), chemical ionization (CI), electron impact (El) or by fast atom bombardment (FAB) methods. Infrared (IR) 15 spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1-mm NaCI cell. Rotations were recorded on a Perkin-Elmer 241 polarimeter. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254). visualized with UV light, 7% ethanolic phosphomolybdic acid or p-anisldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, 20 Merck). <br><br> Products were purified by preparative reversed phase high pressure liquid chromatography (RP-HPLC) using either a Waters Model 3000 Delta Prep equipped with a Delta-pak radial compression cartridge (C18, 300 A, 15m, 47 mm X 300 mm) 25 or a Pharmacia LKB system using Merck Lobar silica or reverse phase C18 columns. Linear gradients were used in all cases and the flow rate was 10-100 mL/minute (to = 5.0 min.). All solvents contained 0.1% TFA. Analytical purity was assessed by RP-HPLC using either a Waters 600E system equipped with a Waters 990 diode array spectrometer (I range 200-400 nM) or a Hewlett Packard seres 30 1050 system equipped with a diode array spectrometer. The stationary phase either a Dynamax C8 column (25 cm x 4.1 mm), a Dynamax 60A C18 column (25 cm x 4.6 mm), a Vydac C18 column (5m. 4.6 mm X 250 mm) or a Rainin C18 column (5m, 4.6 mm X 250 mm). The flow rate was 1.0 to 1.5 ml/min. (tO = 2.8 or 3.0 min.) and the solvent systems were as described below. Enantiomeric purity 35 was assessed using either a Chiralpak AD column (25 cm x 4.6 mm) or a Chiralpak <br><br> Printed from Mimosa <br><br> YvO 97/31907 <br><br> 33 <br><br> PCT/EP97/00916 <br><br> OD column (25cm x 4.6 mm) on either a Hewlet Packard series 1050 HPLC system equipped with a diode array spectrometer or on a Supercritical Fluid (SFC) system using C02 / methanol as the mobile phase. <br><br> 5 INTERMEDIATES <br><br> Intermediate 1 <br><br> 3-(4-benzyloxyphenyi)-2-diazo propionic acid methyl eater <br><br> A solution of 2.5 g (8.77 mmol) O-benzyl tyrosine methyl ester, 1.03 g (8.77 mmol) 10 isoamyl nitrite, and 1.57 g (26.2 mmol) glacial acetic acid in chloroform (65 mL) was stirred and refluxed 15 min and then cooled to RT. The solution was concentrated to an oily residue, dissolved in EtOAc (100 mL), and washed with 5% NaHC03. The organics were then dried (MgS04), filtered, and concentrated to an oily residue which was chromatographed on silica gel u3ing Hexane/EtOAc (1:1) to yield the title 15 compound. 1H NMR (CDCI3) 8 7.43-7.31 (m, 5H) 7.14 (u, 2H. J=8.7) 6.90 (m. 2H) 5.03 (s. 2H) 3.76 (s, 3H) 3.56 (s. 2H). <br><br> Intermediate 2 <br><br> 2-&lt;4-benzyloxybenzyl)-3-hydroxy-3-phenyl-2,3-dihydro-1H-indole-2-carboxylSc 20 acid methyl catsr <br><br> To a refluxing solution of 250 mg (0.84 mmol) of Intermediate 1 and 316 mg (1.59 mmol) 2-aminobenzophenone in toluene (5 mL) was added 1 mg (0.002 mmol, 0.24 equiv) Rhodium(ll) acetate dimer. The resulting solution was refluxed for 10 min, cooled to RT, poured into 2N HCI (10 mL), and extracted with EtOAc. The organics 25 were dried (MgS04), filtered, concentrated, and chromatographed on silica gel using Hexane/EtOAc (3:1) to give the title compound as a yellow oil. 1H NMR (CDCI3) 8 7.62 (s, 1H) 7.60 (s, 1H) 7.43-7.24 (m, 9H) 7.11-7.09 (d. 1H, J = 7.2) 6.92-6.82 (m, 7H) 5.01 (s, 2H) 3.77 (s, 3H) 2.66 (s, 1H) 2.45 (ABq, 2H, JAB=13.5, DnAB= 40.2). <br><br> 30 Intermediate 3 <br><br> 2-(3-Banzoyl-thicphen-2-yl-amino)-3-(4-benzyloxy-phenyl)-propionic acid methyl ester <br><br> 3 mg (0.0067 mmol) rhodiumfll) acetate dimer was added to stirred solution of 300 mg (1.01 mmol) Intermediate 1 (Kawamatsu, Y. at al. Arzneim.-Forsch. 1980, 30(4), 35 585-9) and 110 mg (0.57 mmol) (2-amino-thiophen-3-yl)-phenyl-methanone (Robba, <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 34 <br><br> PCT/EP97/00916 <br><br> M., et al. Bull. Soc. Chim. Fr. 1974, 12(2), 2864-70.) in 10 mL toluene at 80 eC. The mixture was warmed to reflux for 5 min, then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography using CH2CI2 (neat) as eluent to yield 120 mg of the title compound; 5 TLCfCHjClj): Rf=0.40). <br><br> Intermediate 4 <br><br> 2-(2-Benzoyl-thiophen-3-yl-amino)-3-{4-b0nzyloxy-phenyl)-propionic acid methyl ester <br><br> 10 The title compound (280 mg) was preapred from 600 mg (2.02 mmol) of intermediate 1 (Kawamatsu, Y. at al. Arzneim.-Forsch. 1980, 30(4), 585-9) and 203 mg (1.0 mmol) (3-Amino-thiophen-2-yl)-phenyl-methanone (Kiehne, H. (Bayer A.G.) Ger. Offen. 1945964 (March 25, 1971)) according to the method of Intermediate 3 followed by purification via flash chromatography using CH2CI2 (neat) as eluent; 15 TLC(CH2CI2(neat)): Rf=0.45). <br><br> Intermediate S <br><br> N-2-(N-methyl amino ethanol)-1,3-benzoxazole <br><br> To a stirred solution of 10 g (133 mmol) N-methyl aminoethanol at 0*C was dropwise 20 added 10 g (65.2 mmol) 2-chlorobenzoxazole. The resulting solution stirred for 1 h and was diluted with water (250 mL) and extracted with EtOAc. The organics were washed with brine, dried (MgS04), filtered, and concentrated to yield 12.2 g of a tan oil which solidified on standing, m.p. 56-58°C. <br><br> 25 intenwmfr 5 <br><br> N-2-£(N-m«thyl amino* thyl-1-m*thyl«ulfonate)-1,3-benzoxazole] <br><br> To a stirred solution of 22 g (114.6 mmol) of Intermediate 5, and 14.43 g (126 mmol) methanesulfonyl chloride in dichloromethane (100 mL) at 0°C was dropwise added 17.6 mL (126.3 mmol) TEA. The resulting suspension was stirred for 1 h and diluted 30 with water (200 mL) and 1M H3P04 solution (100 mL). The organic phase was separated, dried (MgS04), filtered, and concentrated to yield 20 g of a white solid, m.p. 94-96°C. <br><br> Intermediate 7 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 35 <br><br> PCT/EP97/00916 <br><br> 2-arnino-3-(4-[2-(banzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-propionic acid methyl ester <br><br> To a stirred solution of 3.61 g (18.5 mmol) of (S)-tyrosine methyl ester and 0.81 g ( 20.4 mmol) of sodium hydride (60% suspension in mineral oil) in 50 mL of DMF at 5 RT was added 5.0 g (18.5 mmol) of Intermediate 6. The resulting solution was heated to 100°C for 2 h. After cooling to RT, the solution was quenched with water and extracted with EtOAc. The combined organics were dried (MgS04) and solvent removed in vacuo. The residue was purified by silica gel chromatography using hexane/ EtOAc (gradient of 3:7 to 0:1) as eluent to give 1.45 g (21% yield) of the title 10 compound: low resolution MS (ES) m/e 370 (MH. <br><br> Intermediate 8 <br><br> 2(S)-amino-3-{4-[2-{benzoxazol-2-yl-methyl-a.T:ino)-*thoxy]-phenyl}-propionic acid <br><br> 15 13.5 mL (13.5 mmol) 1 N sodium hydroxide solution was added to a stirred solution of 5.00 g (13.5 mmol) of Intermediate 7 (Faller, A. et. al. WO 94/29285) in 25 mL MeOH, and the resulting solution was stirred for 12 h at room temperature. The MeOH was removed under reduced pressure, and the residue was diluted with 25 mL water. The solution was extracted with 25 mL ether three times, then the 20 aqueous phase was acidified using 14 mL 1 n hydrochloric acid. The resulting white solid was filtered, washed with 3 x 25 mL water and dried under reduced pressure to yield 4.02 g of the title compound; low resolution MS (API+) m/e 356 (MH+). <br><br> Intermediate 9 <br><br> 25 2-diazo-3-{4-{2-(b0nzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-propionic acid methyl ester <br><br> Reaction was performed behind a blast shield. To a stirred solution of 1.45 g of Intermediate 7 and 0.7 mL (11.8 mmol) of glacial acetic acid in 40 mL of chloroform was added 0.5 mL (3.93 mmol) of isoamyl nitrite. The resulting solution was heated 30 to 60°C for 0.25 h. The solution under went a colour change to orange/brown after heating. The solution was cooled to RT and extracted with water and then washed with a saturated solution of sodium bicarbonate. The organics were then dried (MgS04) and the solvent removed in vacuo to quantitatively yield the title compound which was used directly without further purification: low resolution MS (ES) m/e 381 35 (MH+), 353. <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 36 <br><br> Intermediate 10 <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl&lt;amino)-ethoxy]-phenyl)-2-(2-benzoyl-phenylamino)-propionic acid methyl ester <br><br> 5 The title compound (110 mg) was prepared from 0.17 g ( 0.5 mmol) of Intermediate 9 and 0.11 g (0.5 mmol) of 2-amino benzophenone according to the method of Intermediate 3 followed by purification via silica gel chromatography using EtOAc/hexane (gradient of 3:7 to 1:1): low resolution MS (ES) m/e 550 (MH+). <br><br> 10 Intermediate 11 <br><br> 3-{4-[2-(benzoxazol-2-yl-mathyl-amino)-ethoxy]-phenyl}-2-{2-benzoyl-4-methyl-phenylsmino)-propionic acid methyl ester <br><br> The title compound (100 mg) was prepared from 0.13 g ( 0.3 mmol) of Intermediate 9 and 0.10 g (0.5 mmol) of 2-amino-5-methyl benzophenone according to the 15 method of Intermediate 3 followed by purification via silica gel chromatography using EtOAc/hexane (gradient of 3:7 to 1:1): low resolution MS (ES) m/e 564 (MH+). <br><br> Intermediate 12 <br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)&gt;ethoxy]-phenyl}-2-(2-20 cyclohexanecarbonyl-phenylaminoH&gt;ropion(c acid methyl ester <br><br> The title compound (61 mg) was prepared from 125 mg (0.33 mmol) of Intermediate 11 and 87.9 mg (0.46 mmol, 1.4 equiv.) of (2-amino-phenyl)-cyclohexyl-methanone according to the method of Intermediate 3 followed by purification via silica gel flash column chromatography using hexane / EtOAc 3 /1 to 1 /1 as eluent: low resolution 25 MS (API) m/e 556.3 (MH+). <br><br> Intermediate 13 <br><br> 3-{4-[2-Benzoxazol-2-yl-methyl-amino)-«thoxy]-phenyl}-2-(2-benzoyl-thioph8n-3-yiamino)-proplonic acid methyl ester. <br><br> 30 The title compound (130 mg) was prepared from 200 mg (0.53 mmol) of Intermediate 9 and 149 mg (0.74 mmol, 1.4 equiv.) of (3-amino-thiophen-2-yl)-phenyl-methanone according to the method of Intermediate 3 followed by purification via silica gel flash column chromatography using hexane / EtOAc 3 /1 to 1 /1 as eluent: low resolution MS (API) m/e 556.2 (MH+). <br><br> 35 <br><br> Printed from Mimosa <br><br> WO *7/31907 <br><br> 37 <br><br> PCT/EP97/00916 <br><br> Intermediate 14 <br><br> 3-(4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-propionic acid methyl eater. <br><br> To a stirring solution of 1.40 g (7.77 mmol) of methyl 3-(4-hydroxy-phenyl)-propionic 5 acid methyl ester in 15.5 mL of DMF at 0°C was added 310.7 mg (7.77 mmol, 1.0 equiv) of sodium hydride 60% dispersion in oil. The resulting solution was stirred 5 min, and 2.31 g (8.55 mmol, 1.1 equiv.) of Intermediate 6 was added. The resulting solution was allowed to warm to rt and stirred for 19 h, then quenched with HzO. The reaction mixture was extracted with EtOAc. The organic layer was dried 10 (MgS04), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane / EtOAc 1 /1 as eluent afforded 1.61 g of the title compound as a clear oil: low resolution MS (ES) m/e 355 (MH+). <br><br> Intermediate 15 <br><br> 15 3-{4-{2-&lt;Benzoxazol-2-y l-methyl-amino)-ethoxyl-phenyl}-2-benzyl-propionic acid methyl ester. <br><br> To a stirring solution of 502.2 mg (1.42 mmol) of Intermediate 14 in 10 mL of THF at -78 "C was added 1.70 mL (1.70 mmol, 1.2 equiv) of a 1.0 M solution of NaHMDS in THF. The resulting solution was stirred 15 min, and 315.1 mg (1.84 mmol, 1.3 20 equiv.) of benzyl bromide in 4.0 mL of THF was added. The resulting solution was allowed to warm to rt in the bath and stirred for 4 h, then quenched with H20. The reaction mixture was extracted with EtOAc. The organic layer was dried (MgS04), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane / EtOAc 3 / 2 as eluent afforded 90.8 mg of the title 25 compound as a clear oil: low resolution MS (ES) m/e 445 (MH+). <br><br> Intermediate 16 <br><br> 3-{4-{2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-bromo-benzyl)-propionic acid methyl ester. <br><br> 30 To a stirring solution of 1.00 g (2.82 mmol) of Intermediate 15 in 10 mL of THF at -78 °C was added 2.26 mL (3.39 mmol, 1.2 equiv) of a 1.5 M solution of LOA in cyclohexane. The resulting solution was stirred 15 min, and 846.3 mg (3.39 mmol, 1.2 equiv.) of 2-bromo-benzyl bromide in 4.0 mL of THF was added. The resulting solution was allowed to warm to rt in the bath and stirred for 4 h, then quenched with 35 HzO. The reaction mixture was extracted with EtOAc. The organic layer was dried <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 38 <br><br> (MgS04), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane / EtOAc 3 / 2 as eluent afforded 318.5 mg of the title compound as a clear oil: low resolution MS (ES) m/e 523 (MH+). <br><br> 5 Intermediate 17 <br><br> {4-{2-{methyl-pyridin-2-yt-amino)-ethoxy]-phenylHVtoOH <br><br> Sodium borohydride (0.5 g, 13.2 mmol) was added to stirred solution of 5.12 g (20 mmol) 4-[2-(methyl-pyridin-2-yl-amino)-ethoxy}-benzaldehyde (Cantello, B. C. C. et al. J. Med. Chem. 1994, 37, 3977-85) in 50 mL anhydrous ethyi aicohol. The mixture 10 was stirred at 20 *C for 2 h. 10 mL water was added to the mixture, and it was stirred for 30 min. The ethyl alcohol was removed under reduced pressure, 50 mL water and 100 mL diethyl ether was added to the residue. The mixture was stirred for 30 min, then an additional amount of 100 mL ether was added. The phases were separated, the organic phase was extracted with 100 mL water three times, dried 15 with anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure to provide 5.06 g of the title compound: TLC (Hexane/EtOAc(1:1)): Rf=0.50). <br><br> Intermediate 18 <br><br> 20 [2-{4-Bromomethyl-phenoxy)-«thyl)-methyl-pyridln-2-yl-amir&gt;e <br><br> Triphenyl phosphine dibromide (422 mg, 1.0 mmol) was added to a stirred solution of 258 mg (1 mmol) of Intermediate 17 in 10 mL methylene chloride at 5 °C. The mixture was stirred for 30 min, and it was allowed to warm up to 20 "C, then an additional 422 mg (1 mmol) triphenyl phosphine dibromide was added in one portion. 25 The mixture was stirred for an additional 30 min. then 20 mL methylene chloride was added, and the solution was cooled to 0 °C. 30 mL saturated sodium bicarbonate aq. solution was added to the mixture, and then it was stirred for 30 min. The phases were separated, the aqueous phase was extracted with 20 mL methylene chloride twice, then the organic phases were combined, dried with anhydrous magnesium 30 sulfate and filtered. The filtrate was concentrated under reduced pressure while the temperature was kept below 20 "C. The residue was purified by flash chromatography using hexane/EtOAc(4:1) as eluent. The fractions were concentrated under reduced pressure at 15-20 °C to yield 260 mg of the title compound: TLC (Hexane/EtOAc(1:1)): Rf=0.90). <br><br> 35 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 39 <br><br> Intermediate 19 <br><br> 2-Benzhydrylideneamino-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-pheny?}-propionic acid ethyl ester <br><br> A solution of 4.0 g (71.4 mmol) potassium hydroxide in 4 mL water was added to a 5 cooled (0 °C) solution of 3.50 g (10.9 mmol) of Intermediate 18, 3.70 g (13.8 mmol) N-(Diphenylmethytene)-glycine ethyl ester and 4.3 g (16.1 mmol) tetrabutylammonium hydrogen sulfate over 5 min. The resulting yellow mixture was stirred for 1 hour at 5-10 °C. then 10 g anhydrous magnesium sulfate was added, and the suspension was filtered. The filtrate was concentrated under reduced 10 pressure without using external heat. The residue was transferred to a silica gel packed column which was prewashed with a solvent mixture containing Hexane/EtOAc/NEt3(40:10:1). Purification by flash chromatography using hexane/EtOAc (4:1) then hexane/EtOAc (2:1) resulted in 5.66 g of the title compound: TLC (Hexane/EtOAc(5:1)): Rf=0.30). <br><br> 15 <br><br> Intermediate 20 <br><br> 2-Amlno-3-{4-[2-(m«thyl-pyridln-2-yl-«mino)-«thoxy]-phenyl)-proplonic acid ethyi ester <br><br> To a stirred solution of 5.66 g (11.1 mmol) of Intermediate 19 in 200 mL ethanol, 20 20 mL conc. hydrochloric acid was added at 20 °C over 15 min, and the mixture was stirred at room temperature for one hour. 400 mL saturated sodium bicarbonate solution was added dropwise to the solution, and when the carbon dioxide evolution stopped 200 ml. methylene chloride was added. The phases were separated, and the aqueous phase was extracted with 100 mL methylene chloride three times. The 25 organic phases were combined, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography using hexane/EtOAc(1:1), EtOAc(neat), then EtOAc/EtOH (9:1) solvent mixtures as eluent to yield 3.19 g of the title compound: TLC (Hexane/EtOAc( 1:1)): Rf=0.10). <br><br> 30 <br><br> Intermediate 21 <br><br> 3-Hydroxy-2-{4-[2-{methyl-pyridin-2-yl-amino)-ethoxy]-b9nzyl}-3-ph»nyl-2f3-dihydro-1H-indole-2-carboxylic acid ethyl ester <br><br> The title compound (310 mg) was prepared from 291 mg (0.85 mmol) of 35 Intermediate 20 according to the method of Intermediate 1 followed by reaction with <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/009J6 <br><br> 40 <br><br> 197 mg (1 mmol) 2-aminobenzophenone according to the method of Intermediate 3 followed by purification via silica gel flash chromatography using hexane-EtOAc(4:1) then hexane:EtOAc(1:1) as eluent: low resolution MS (ESP+) m/e 524 (MH+). <br><br> 5 Intermediate 22 <br><br> 2-Amino-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic ac!d To a stirred solution of 160 mg (0.46 mmol) of Intermediate 20 in 3.2 mL MeOH, 112 mg (2 mmol) potassium hydroxide was added in 1 mL water. The mixture was stirred 5 h at 20 *C, then the MeOH was removed under reduced pressure. 240 mg (2 10 mmol) sodium bisulfate was added to the mixture in 5 mL water and the slurry was stirred at 20 "C for 30 min. The precipitate was filtered, and wushed with 5 mL water three times. The filtrate was adjusted to pH=5 using saturated sodium bicarbonate solution, and the precipitate was filtered, and washed with 5 mL water three times. The solids were combined and dried under reduced pressure to yield 115 mg of the 15 title compound: TLC (EtOH(neat)): Rf=0.05). <br><br> Intermediate 23 <br><br> (S)-2-(2-Benzoyl-phenylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester <br><br> 20 A stirred mixture of 92 g (0.45 mol) 2-benzoyl-cyclohexanone, (Denny, W. A. et. al. J. Med. Chem. 1978, 21(5), 430-7) 78 g (0.40 mol) L-Tyrosine methyl ester, 17.0 g Palladium on activated carbon (10%) was refluxed for 2 h in 1 L anisoie while the resulting water was removed by a Dean-Stark apparatus. The mixture was cooled to 60 *C and the Pd/C was filtered, and washed with 50 mL anisoie three times. The 25 mixture was cooled to 40 "C, 1L hexane was added and kept at -20 °C for 48 h. The solid was filtered, washed with 200 mL hexane five times to yield 89.0 g crude (S)-2-(2-Benzoyl-phenylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester. This solid was mixed with 220 mL of MeOH, and the slurry was refluxed for 30 min. The mixture was cooled to 0 °C, the product was filtered and washed with 50 mL cold (-30 20 °C) MeOH twice, then dried under reduced pressure to yield 67.4 g the of the title compound, mp 185-6 "C; low resolution MS (ESP+) m/e 376 (MH+). <br><br> Intermediate 24 <br><br> 2-&lt;N-tert-butoxycarbonyl-N-methyl-amino)ethanol <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 41 <br><br> PCT/EP97/00916 <br><br> A solution of 10 g (0.133 moi) of 2-(methylamino)ethanol in 266 mL of CH2CI2 at 25*C was treated with 29.1 g (0.133 mol) of B0C20. After stirring for 3 h, the reaction was concentrated in vacuo. Purification by silica get chromatography eluting with hexanes/EtOAc (1:1 /E 1:2 /E 1:4) gave rise to 23.3 g (100%) of title 5 compound as a clear oil: low resolution MS (ES) m/e 198 (MNa+). <br><br> Intermediate 25 <br><br> 2(SH2-beruoyl-phenylamlno)-3-(4-[2-{t»rt-butoxycarbonyl-methyl-amino)-•thoxy]-phenyl)-propionlc acid methyl ester <br><br> 10 A solution of 1.5 g (3.99 mmol) of Intermediate 23, 770 mg (4.39 mmol, 1.1 equiv) of Intermediate 24 and 1.57 g (5.99 mmol, 1.5 equiv) of triphenylphosphine in 40 mL of THF at 25°C was treated dropwise with 0.944 mL (5.99 mmol, 1.5 equiv) of DEAD. The reaction was stirred at 25°C for 48 h then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexanes/EtOAc (2:1) 15 as eluent to give 1.37 g (65%) of title compound as a viscous yellow oil: low resolution MS (ES) m/e 555 (MNa+), 533 (MH+). <br><br> Intermediate 26 <br><br> 2(SH2-bsnzoy)-phenyiamino)-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-20 phenyl}-propionic acid methyl ester <br><br> A solution of 2.56 g (4.81 mmol) of Intermediate 25 in 56 mL of CH2CI2 at 25°C was treated with 56 mL (0.73 mol, 152 equiv) of TFA. After stirring for 30 min, the solution was neutralized with saturated NaHC03 followed by solid NaHC03 and extracted with CH2Ci2. The combined organics were dried (Na2S04), filtered, and 25 concentrated in vacuo. The crude amine was used immediately in the next reaction. A solution of 2.08 g (4.81 mmol) of the crude amine from above in 480 mL of 2-fluoropyridine was allowed to reflux for 16 h then concentrated in vacuo. Purification by silica gel flash column chromatography using hexanes/EtOAc (2:1) as eluent provided 1.85 g (76%) of the title compound as a yellow oil: low resolution MS (CI) 30 m/e 511 (MH+), 510 (M+). <br><br> Intermediate 27 <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl«amino)-«thoxy]-phenyl}-2(SM2-benzoyl-phenylamino)-propionic acid methyl ester <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 42 <br><br> PCT/EP97/00916 <br><br> A solution of 319 mg (0.60 mmol) of Intermediate 25 in 7 mL of CH2CI2 at 25"C was treated with 7 mL (90.9 mmol, 152 equiv) of TFA. After stirring for 30 min, the solution was neutralized with saturated NaHC03 and extracted with CH2CI2. The combined organics were dried (Na2S04), filtered, and concentrated in vacuo. To a 5 solution of 259 mg (0.60 mmol) of the above amine in 6 mL of THF at 25°C was added 0.250 mL (1.60 mmol, 3 equiv) of Et3N followed by 0.103 mL (0.90 mmol, 1.5 equiv) cf 2-chiorobenzoxazole. After stirring fro 24 h, the reaction was diluted with EtOAc, poured into saturated NaHC03, and extracted with EtOAc. The combined organics were dried (Na2S04), filtered, and concentrated in vacuo. Purification by 10 silica gel flash column chromatography eluting with hexanes/EtOAc (2:1 /E 1:1) provided 244 mg (74%) of title compound as a yellow solid: low resolution MS (ES) m/e 572 (MNa+), 550 (MH+). <br><br> Intermediate 28 <br><br> 15 Toluene-4-sulfonic acid 1-benzoxazol-2-yl-pyrrolidin-2S-ylmsthyl ester <br><br> To a solution of 1.0 g (9.89 mmol) of L-prolinol in 19.8 mL of THF at 0°C was added 3.0 mL (21.8 mmol, 2.2 equiv) of Et3N followed by 1.24 mL '10.Fi mmol, 1.1 equiv) of 2-chlorobenzoxazole. The reaction was filtered washing with THF, and the filtrate was concentrated in vacuo. The residue was dissolved in 10 mL of pyridine and 20 treated with 1.9 g (9.89 mmol, 1 squiv) of p-toluenesulfonyl chloride. After stirring for 24 h, the reaction was poured into H20, and the product was extracted with EtOAc. The combined organics were dried (MgS04), filtered, and concentrated in vacuo. Purification by silica gel flash column chromatography eluting with hexanes/EtOAc (2:1) gave rise to 2.76 g (75%) of title compound as a white solid: 1H NMR (CDCI3, 25 300 MHz) d 7.67 (d, 2H, J = 12.3), 7.33-6.94 (m, 6H), 4.46 (dd, 1H, J = 7.8, 16.2), 4.30-4.10 (m, 2H), 3.60 (m, 2H), 2.16 (s. 3H). 2.25-1.90 (m. 4H); low resolution MS (ES) m/e 395 (MNa+), 373 (MH+); Anal. (C19H20N2O4S) Calud. C, 61.27; H, 5.41; N, 7.52; S. 8.61 Found C. 61.20; H, 5.46; N, 7.46; S, 8.55; TLC (hexanes/EtOAc (2:1)): Rf= 0.28. <br><br> 30 <br><br> Intermediate 29 <br><br> Toluene-4-sutfonic acid 1-benzoxazol-2-yl-pyrrolidin-2R-ylmathyl ester <br><br> The title compound (1.6 g) was prepared from 1.0 g (9.89 mmol) of D-prolinol according to the method of Intermediate 28 followed by purification via trituration of <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 43 <br><br> PCT/EP97/00916 <br><br> the solid with hexanes/EtOAc (1:1): low resolution MS (ES) m/e 395 (MNa+), 373 (MH+). <br><br> Intermediate <br><br> 5 3-[4-(1-benK&gt;xazol-2-yJ)-pyrrolidin-2S-yl-methoxy)-phenyl]-2-(2-benzoyl-phenylamino)-propionic acid methyl ester <br><br> A solution of 2.0 g (5.33 mmol) of Intermediate 23 and 1.98 g (5.33 mmol, 1 equiv) of Intermediate 28 in 21.3 mL of OMF at 25°C under nitrogen was treated with 2.08 g (6.4 mmol, 1.2 equiv) of Cs2C03. The reaction was heated to 809C and stirred 24 10 h. Upon cooling to 25aC, the reaction was poured into H20 and hexanes/EtOAc (1:1) and extracted with hexanes/EtOAc (1:1). The combined organics were dried (Na2S04), filtered, and concentrated in vacuo. Purification by silica gel flash column chromatography eluting with hexanes/EtOAc (1.5:1) gave rise to 2.26 g (74%) of the title compound as a yellow solid: low resolution MS (ES) m/e 598 (MNa+), 576 15 (MH+). <br><br> Intermediate 31 <br><br> 3-{4-{1-benzoxazol-2-yl)-f.yiTolidin-2R-yl-methoxy)-phenylJ-2-{2-b«nzoyl-ph«nylamino)-propionic acid methyl ester <br><br> 20 The title compound (285 mg) was prepared from 0.25 g (0.67 mmol) of Intermediate 23 and 0.248 g (0.67 mmol. 1 equiv) of Intermediate 29 according to the method of Intermediate 30 followed by purification via silica gel flash column chromatography eluting with hexanes/EtOAc (1.5:1): low resolution MS (ES) m/e 598 (MNa+). 577 (MH+). <br><br> 25 <br><br> intermediate 32 <br><br> 1 -Benzoxazol-2-y l-pyrrolidin-3-ol <br><br> To a stirring solution of 5.1 mL (44.6 mmol) of 2-chlorobenzoxazole in 35 mL of THF at 0°C was added 4.28 g (49.0 mmol, 1.1 equiv.) of (R)-3-hydroxypyrrolidine and 30 4.42 mL (32 mmol, 0.72 equiv.) of triethylamine. The resulting solution was stirred 12h at RT, the precipitate was filtered, washed with THF (3X5 mL), and the filtrate concentrated in vacuo. Purification by silica gel flash column chromatography using hexane / EtOAc 1 /1 tc EtOAc as eluent afforded 3.74 g of the title compound: low resolution MS (ESP) m/e 205 (MH+). <br><br> 35 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 44 <br><br> Intermediate 33 <br><br> rtfethanesulfonic acid 1-banzoxazol-2-yl-pyrrolidin-3-yl ester <br><br> To a stirring solution of 3.74 g (18.3 mmol) of Intermediate 32 in 30 mL of pyridine was added 1.37 mL (17.8 mmol, 0.93 equiv.) of methanesulfonyl chloride . The 5 resulting solution was stirred 3h at RT then quenched into ice water (100 mL). The reaction mixture was extracted with DCM (3 X 50 mL). The combined organic extracts were washed successively with saturated NaHC03, brine, dried (MgS04), and the solvents removed in vacuo. Purification by trituration with isopropyl alcohol afforded 3.71 g of the title compound: low resolution MS (ESP) m/e 283 (MH+). <br><br> 10 <br><br> Intermediate 34 <br><br> 3-{4-(1'Benzoxa2ol-2&gt;yl-pyiTolidin-3-yloxy)-phenyl]-2-(2-b0nzoyl-phenylamino)-propionic acid methyl ester <br><br> The title compound (156 mg) was prepared from 188 mg (0.50 mmol) of 15 Intermediate 23 and 155 mg. (0.55 mmol, 1.1 equiv.) of Intermediate 33 according to the method of Intermediate 30 followed by purification via silica gel flash column chromatography using hexane / EtOAc 3 / 1 to 1 / 1 as eluent: iow resolution MS (ESP) m/e 562 (MH+). <br><br> 20 Intermediate 35 <br><br> 2(S)-(2-Benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-«thoxy]&gt; phenyl}-propionic acid methyl ester <br><br> A solution of 0.25 g of Intermediate 23 (0.67 mmol), 0.20 g of 2-(5-methyl-? phenyloxazol-4-yl)ethanol (0.98 rcnol, 1.5 equiv, Maybridge), and 0.35 g of 25 triphenylphosphine (1.33 mmol, 2.0 equiv) in 10 mL of anhydrous THF was cooled to 0CC and treated with 0.21 mL of diethyl azodicarboxylate (1.33 mmol, 2.0 equiv). The reaction was allowed to warm to RT for 18 h, concentrated in vacuo purified by flash chromatography on silica gel (7:3 hexane:EtOAc). This afforded 0.26 g (70%) of the title compound as a yellow foam: mp 55-60°C; low resolution MS (ES) m/e 30 561 (MH+). <br><br> Intermediate 36 <br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(4-chlorophenyl)-thiazol-4ylmethoxy]-phenyl}-propionic acid methyl ester <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 45 <br><br> PCT/EP97/00916 <br><br> The title compound (210 mg) was prepared from 150 mg (0.40 mmol) of Intermediate 23 and "&gt;07 mg (0.44 mmol, 1.1 equiv) of 4-chloromethyl-2-(4-chlorophenyl)thiazole according to the method of Intermediate 30 followed by purification via silica gel flash column chromatography using hexane / EtOAc 8 /1 as 5 eluent: low resolution MS (FAB)m / e 584 (MH+). 583 (M+). <br><br> Intermediate 37 <br><br> 2-(2-B«nzoyl-phenylamino)-3-{4-(2-hydroxy-ethoxy)-phenyl]-proplonic acid methyl eater <br><br> 10 A suspension of 400 mg (1.06 mmol) of Intermediate 23, 930 mg (10.60 mmol, 10.0 equiv) of ethylene carbonate, and 175 mg (1.28 mmol, 1.2 equiv) of K2C03 in 10 mL of DMF was heated to 95 °C for 3 h with stirring. The reaction mixture was cooled to RT, poured into 100 mL of Et20 and extracted with H20 (2 x 50 mL). The organic layer was separated, dried (MgS04), and the solvents removed in vacuo. 15 Purification of the yellow solid by silica gel flash column chromatography using hexane / EtOAc 2 / 1 as eSuent afforded 440 mg of the title compound as a clear yellow oil: 1H NMR (CDCI,, 300 MHz) S 8.90 (d, 1H, J = 7.5), 7.60 (m, 2H), 7.52-7.31 (m, 5H), 7.20 (dd, 2H, J - 2.2, 6.5), 6.83 (dd, 2H, J - 2.2, 6.5), 6.60 (m, 2H), 4.51 (s, 1H), 4.38 (dd, 1H, J - 5.9, 5.9), 4.04 (m, 2H), 3.94 (m, 2H), 3.70 (s. 3H), 20 3.17 (m,2H). <br><br> Intermediate 38 <br><br> 2-{2-Benzoyl-phenylamino)-3-[4-(2-methan*8ulfonyloxy-ethoxy)-phenyl]-propionic acid methyl eater <br><br> 25 To a stirring solution of 350 mg (0.83 mmol) of Intermediate 37 in 8 mL of THF at RT was added 0.23 mL (1.67 mmol, 2.0 equiv) of Et3N, followed by 0.13 mL (1.67 mmol, 2.0 equiv) of methanesulfonyl chloride. The resulting mixture was stirred 90 min at RT then heated to 45 °C for 1 h. The reaction mixture was cooled to RT, poured into 50 mL of Et20 and extracted with H20 (2 x 50 mL). The organic layer was 30 separated, dried (K2C03), and the solvents removed in vacuo to afford 430 mg of the title compound as a clear yellow oil, which was used without further purification: low resolution MS (Cl)m / e 499 (MH+), 498 (M+). <br><br> Intermediate 39 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 46 <br><br> 3-{4-[2-{2-Amlno-phenylamlno-ethoxy]-phenyl}-2-{2-benzoyl-phenylamino)-propionic acid methyl eater <br><br> To a stirring solution of 425 mg (0.85 mmol) of intermediate 38 in 5 mL dry DMF at RT was added 560 mg (4.27 mmol, 5.0 equiv) of K2C03 and 462 mg (4.27 mmol, 5.0 5 equiv) of 1,2-phenylenediamine. The resulting solution was heated to 80 °C for 17 h. The reaction mixture was cooled to RT, poured into 50 mL of Et20 and extracted sequentially with 1 N HCI (1 x 20 mL). NaHC03 (1 x 20 mL), and HzO (2 x 50 mL). The organic layer was separated, dried (K2C03), and the solvents removed in vacuo. Purification of the crude material by silica gel flash column chromatography using 10 hexane / EtOAc 2 / 1 as eluent afforded 90 mg of the title compound as a clear yellow oil which discolored upon standing and should be used immediately after purification: low resolution MS (Cl)m ie 511 (MH+), 510 (M+). <br><br> Intermediate 4P <br><br> 15 3-{4-(2-Benzolmldazol-1 -yl-ethoxy)-phenyl]-2-(2-benzoyl-phanylam!no)-propionic acid mathyl eater <br><br> To a stirring solution of 90 mg (0.18 mmol) of Intermediate 39 in 3 mL of triethyl orthoformate was added 5 mg of p-toluenesulfonic acid, which produced a white precipitate. This suspension was heated to 80 °C for 2 h with stirring, during which 20 much of the precipitate disappeared. The reaction mixture was cooled to RT, poured into 20 mL of Et20 / dichloromethane 1:1 and extracted with 1 N NaOH (1 x 20 mL). The organic layer was washed with H20 (1 x 20 mL). separated, dried (MgS04), and the solvents removed in vacuo. Purification of the crude product by silica gel flash column chromatography using EtOAc as eluent afforded 94 mg of the 25 title compound as a clear yellow oil: lew resolution MS (Cl)m / e 521 (MH+), 520 (M+). <br><br> Intormttiiift 41 <br><br> 1 -&lt;3-iodo-phenyl)-butane*1,3-dione <br><br> 30 4.0 g (100 mmol) sodium hydride (60%) was added to a stirred solution of 13.8 g (50 mmol) 3-iodobenzoic acid ethyl ester and 12 mL (160 mmol) acetone in 25 mL anhydrous THF. The mixture was stirred at 25 eC for 20 min, then slowly warmed to 30 °C. An exothermic reaction started, and the temperature was kept below 30 °C with water bath. After 1 h the hydrogen evolution stopped, and the mixture was 35 cooled to 5 °C, and quenched with 150 mL 3 % aqueous hydrochloric acid. 200 mL <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 47 <br><br> PCT/EP97/05W16 <br><br> ether was added to the solution, then the phases were separated. The organic phase was washed with 100 mL water three times, dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was mixed with 200 mL hexane, then the precipitate was filtered, and 5 washed with 50 mL hexane three times. The filtrate was concentrated under reduced pressure, and purified by silica gel flash chromatography with hexane(neat), then hexane-EtOAc(4:1) as eluents to yield 7.0 g of the title compound, which was crystallized from hexane at -40 °C; TLC (Hexane-EtOAc(4:1)): Rf=0.65). <br><br> 10 Intermediate 42 <br><br> [2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yn-acetic acid methyl ester <br><br> A mixture of 725 mg (4.80 mmol) of 4-methoxybenzamide and 1.0 g (4.80 mmol) of methyl 4-bromo-3-oxo-pentanoate was heated neat at 120 aC for 2 h. The resulting dark slurry was cooled to RT, diluted with 2 mL of dichloromethane and purified by 15 silica gel flash column chromatography using hexane / EtOAc 3 / 1 as eluent to afford 189 mg of the title compound as a yellow solid: low resolution MS (FAB)m /e 285 (MH+), 284 (M+). <br><br> 20 2-{2-&lt;4-methoxy-ph«nyl)-5-methyl-oxazol-4-yl]-ethanol <br><br> To a stirring solution of 185 mg (0.71 mmol) of Intermediate 42 in 5 mL of THF at 0 "C was added 0.71 mL (0.71 mmol, 1.0 equiv) of a 1.0 M solution of LiAIH4 in THF. The resulting solution was stirred at RT for 45 min then cooled to 0 °C and quenched by careful addition of 0.027 mL of H-O, followed by addition of 0.027 mL 25 of 15% NaOH and 0.080 mL of H20. The resulting slurry was filtered to remove the solids and the filtrate was concentrated in vacuo to afford 164 mg of the title compound as a light yellow oil: 'h NMR (CDCIs, 400 MHz) 5 7.92 (d, 2H, J = 8.8), 6.94 (d, 2H, 8.8), 3.92 (dt. 2H, J = 5.7, 11.5). 3.86 (s. 3H), 3.35 (t. 1H, J = 6.2). 2.71 (t, 2H, J = 5.7), 2.32 (s, 3H). <br><br> 30 <br><br> Intermediate 44 <br><br> 2(S)-(2-benzoyl-ph®nylamino)-3-{4-[2-(5-methyl-2-{4-methoxy)-phenyl-oxazol-4-yl)-ethoxy]-phenyl)-propionic acid methyl ester <br><br> To a stirring solution of 195 mg (0.74 mmol, 1.05 equiv) of triphenylphosphine in 5 35 mL of THF at 0 °C was added dropwise 117 mg (0.67 mmol, 0.95 equiv) of diethyl <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 48 <br><br> azodicarboxylate. The resulting light yellow solution was stirred at RT for 5 min then added dropwise to a solution of 265 mg (0.71 mmol) of Intermediate 23 and 165 mg (0.71 mmol) of Intermediate 43 in 5 mL of THF. The resulting solution was stirred 18 h at RT and then the solvent was removed in vacuo. The residue was stirred 5 vigorously for 1 h in 30 mL of 2:1 diethyl ether /1 N LiOH biphasic solution to effect selective removal of residual Intermediate 23. The layers were separated and the organic layer washed with HzO, dried (MgS04), and solvent removed in vacuo. Purification of the yellow solid by silica gel flash column chromatography using hexane / EtOAc 2 /1 as eluent afforded 200 mg of the title compound as a yellow 10 solid: low resolution MS (FAB)m/e 591 (MH+). <br><br> Intermediate 45 <br><br> [2-&lt;4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ac«tic acid methyl ester <br><br> A solution of 667 mg (4.80 mmol) of 4-fluorobenzamide and 1.0 g (4.80 mmol) of 15 methyl 4-bromo-3-oxo-pentanoate in 6 mL of dry toluene was heated at 120 'C for 16 h. The resulting dark slurry was cooled to RT, diluted with 10 mL of EtOAc, and washed with NaHC03 (1 x 10 mL). The organic layer was separated, dried (MgS04), and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using hexane / EtOAc 4 / 1 as eluent to afford 308 mg of 20 the title compound as a clear oil: 1H NMR (CDCI3. 400 MHz) 8 7.97 (m, 2H), 7.11 (m, 2H), 3.73 (s. 3H), 3.56 (s, 2H), 2.36 (s, 3H). <br><br> Intermediate 46 <br><br> 2-{2-(4-fluoro-ph«nyl)-5-methyl-oxazoM-yl]-ethanol <br><br> 25 The title compound was prepared from 300 mg (1.20 mmol) of Intermediate 45 by the procedure for preparing Intermediate 43 to afford 248 mg of the title compound as a white solid: low resolution MS (FAB)m /e 221 (M ). <br><br> Intermediate 47 <br><br> 30 2(S)-(2-benzoyl-ph0nylamino)-3-{4-[2~(5-methyl-2-(4-fluoro)-phenyl-oxazot-4-yl)-•thoxy]-phenyl)-propionic acid methyl ester <br><br> The title compound (298 mg) was prepared from 407 mg (1.08 mmol) of Intermediate 23 and 240 mg (1.08 mmol) of Intermediate 46 according to the method of Intermediate 44 followed by purification via silica gel flash column <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 49 <br><br> PCT/EP97/00916 <br><br> chromatography using hexane / EtOAc 2 /1 as eluent: low resolution MS (FAB)m /e 580 (MH ), 579 (M*). <br><br> Intermediate 48 5 2-{5-methyl-1 -phany!-1 H-pyrazol-3-yl)-ethanol <br><br> To a stirring solution of 150 mg (0.96 mmul) of methyl 3,5-dioxohexanoate in 5 mL of MeOH at RT was added 104 mg (0.96 mmol) of phenylhydrazine followed by 10 mg of p-toluenesulfonic acid. The reaction mixture was stirred 15 min at RT then refluxed for 2 h. The reaction was cooled to RT, diluted with 10 mL of EtOAc, and 10 washed with NaHC03 (1x10 mL). The organic layer was separated, dried (MgS04), and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using hexane / EtOAc 3 / 1 as eluent to afford 180 mg of the cyclized methyl ester. This material was then reduced according to the procedure outlined for the preparation of Intermediate 43: H NMR (CDCI3, 400 15 MHz) 8 7.41 (m, 5H). 6.10 (s, 1H), 3.81 (t, 2H. J = 6.5), 2.89 (t. 2H. J = 6.5), 2.32 (s, 3H). <br><br> Intermediate 49 <br><br> 2(SM2*benzoyl-phenylamino)-3-{4-[2-{5-methyM-phenyMH-pyrazol-3-yl)-20 ethoxy]-phanyl}-propionic acid methyl ester <br><br> The title compound (100 mg) was prepared from 275 mg (0.74 mmol) of Intermediate 23 and 150 mg (0.74 mmol) of Intermediate 48 according to the method of Intermediate 44 followed by purification via silica gel flash column chromatography using a gradient elution of hexane / EtOAc 4 /1 to hexane / EtOAc 25 2 /1 as eluent: low resolution MS (FAB)m/e 561 (MH*), 560 (M). <br><br> Intermediate SO <br><br> [2-{2-plp0radin-1-yl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester <br><br> A mixture of 1.72 g (13.40 mmol, 4.0 equ&gt;v) of 1-piperidine carboxamide and 700 mg 30 (3.35 mmol) of methyl 4-bromo-3-oxo-pentanoate in 3 mL of dry DMF was heated at 120 °C for 15 h. The resulting dark sluny was cooled to RT, diluted with 10 mL of EtOAc, and washed with H20 (1 x 10 mL). The organic layer was separated, dried (MgS04), and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using hexane / EtOAc 2 /1 as eluent to afford 192 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/009S6 <br><br> 50 <br><br> mg of the title compound as an orange oil: low resolution MS (FAB)m / e 240 (MH*), 239 (M ). <br><br> intermediate 51 5 2-[5-methy l-2-piperidin1 -yl-oxazol-4-y i]-ethanol <br><br> The title compound (145 mg) was prepared from 190 mg (0.80 mmol) of Intermediate 50 according to the method of Intermediate 43: H NMR (CDCI3, 400 MHz) 5 5.03 (t, 1H, J= 5.8), 3.90 (d. 2H, 5.9), 3.73 (m, 4H). 2.83 (t. 2H, J= 5.9). 2.19 (s, 3H), 1.71 (m. oH). <br><br> 10 <br><br> Intermediate 52 <br><br> 2(S)-(2-b«nzoyl-ph*nylamino)-3-{4-[2-{5-m«thyl-2-pip«ridin-1-yl-oxazol-4-vl&gt;-ethoxy]-phenyl}-propionic acid methyl ester <br><br> The title compound (280 mg) was prepared from 250 mg (0.67 mmol) of 15 Intermediate 23 and 140 mg (0.67 mmol) of Intermediate 51 according to the method of Intermediate 44 followed by purification via silica gel flash column chromatography using hexane / EtOAc 2 /1 as eluent: low resolution MS (FAB)m / e 568 (MH+), 567 (M+). <br><br> 20 Intermediate 53 <br><br> 1-Morpholine thiocarboxamide <br><br> To a stirring solution of 2.0 g (11.20 mmol, 1.15 equiv) of thiocarbonyldiimidazole in 30 mL of THF at RT was added 932 mg (10.70 mmol) of morpholine. The reaction mixture was stirred at RT for 2 h then heated to 55 *C for 1 h. The reaction mixture 25 was cooled to RT and approximately 20 mL of THF was removed in vacuo, and then 10 mL of a 2.0 M solution of ammonia in MeOH was added and the reaction mixture was sealed and stirred 15 h. An additional 10 mL of 2.0 M ammonia in MeOH was then added and the reaction stirred in a warm water bath for 8 h, during which time a white precipitate appeared. The precipitate was filtered, rinsed with diethyl ettv 30 collected and dried to provide 745 mg of the title compound: low resolution (FAB)m/e 147 (MH ). <br><br> Intermediate 54 <br><br> 2-(2-morpholin-4-yl-5-methyl-thiazol-4-yl)-acetic acid methyl ester <br><br> Frinted from Mimosa <br><br> WO 97/31907 <br><br> 51 <br><br> PCT/EP97/00916 <br><br> A mixture of 375 mg (2.56 mmol) of Intermediate 53 and 536 mg (2.56 mmol) of methyl 4-bromo-3-oxo-pentanoate in 5 mL of absolute ethanol was refluxed for 5 h. The reaction was cooled to RT, and the ethanol removed in vacuo. The residue was diluted with 10 mL of EtOAc, and washed with NaHCOa (1 x 10 mL). The organic 5 layer was separated, dried (MgS04), and the solvents removed in vacuo. Purification of the material by silica ge! flash column chromatography using hexane / EtOAc 2 M as eluent to afford 590 mg of the title compound as a clear oil: H NMR (CDCIa, 400 MHz) 8 3.79 (m. 4H), 3.69 (s, 3H), 3.47 (s. 2H). 3.38 (m, 4H), 2.23 (s, 3H). <br><br> 10 <br><br> Intermediate SS <br><br> 2-[5-methyl-2-morpholin-1 -yl-oxazol-4-yll-«than &gt;1 <br><br> The title compound (487 mg) was prepared from 590 mg (2.27 mmol) of Intermediate 54 according to the method of Intermediate 43: H NMR (COCI3, 400 15 MHz) 5 4.29 (t. 1H. J = 5.9), 3.90 (d, 2H, J = 5.9), 3.82 (m. 6H), 3.37 (m, 4H), 2.68 (t, 2H, J = 5.4), 2.22 (s, 3H). <br><br> Intermediate 56 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-morpholin-4-yl-thiazol-4-yl)-20 •thoxy]-phenyl)-propionic acid methyl ester <br><br> The title compound (810 mg) was prepared from 760 mg (2.02 mmol) of Intermediate 23 and 480 mg (2.02 mmol) of Intermediate 55 according to the method of intermediate 44 followed by purification via silica gel flash column chromatography using hexane / EtOAc 2 /1 as eluent: H NMR (CDCI3, 400 MHz) 8 25 8.89 (d, 1H, J- 7.3), 7.53 (d, 2H, J = 8.6) 7.47 (m, 3H), 7.33 (dd, 1H, J = 7.2, 7.2), 7.17 (d, 2H, J = 8.6), 6.81' (d, 2H, J = 8.6), 6.63 (d, 1H, J = 8.5), 6.57 (dd. 1H, J = 7.5, 7.5), 4.37 (dd, 1H, J = 7.2, 13.3), 4.15 (t, 2H, J = 7.1), 3.78 (m, 4H), 3.69 (s, 3H). 3.36 (m. 4H), 3.19 (dd, 1H, J = 6.0, 13.9), 3.11 (dd, 1H, J =7.3, 13.9), 2.93 (t, 2H, J = 7.1), 2.23 (s, 3H). <br><br> 30 <br><br> Intermediate 57 <br><br> [2-(2-pyrindin-4*yl)-5-methyl-thiazol-4-yl]-ac8tic acid methyl ester <br><br> A mixture of 800 mg (5.79 mmol) of thioisonicotinamide and 1.21 g (5.79 mmol) of methyl 4-bromo-3-oxo-pentanoate in 20 mL of toluene I absolute ethanol 1:1 was 35 heated to 100 "C for 18 h. The reaction was cooled to RT, diluted with 20 mL of <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 52 <br><br> EtOAc, and washed with NaHC03 (1 x 10 mL). The organic layer was separated, dried (MgS04), and the sclents removed in vacuo. Purification of the material by silica gel flash column chromatography using hexane / EtOAc 1 / 1 as eluent afforded 630 mg of the title compound as an orange solid: H NMR (CDCI3, 400 5 MHz) S 8.64 (d, 2H, J = 6.1), 7.70 (d, 2H, J = 6.1), 3.82 (s, 2H). 3.71 (s. 3H), 2.45 (s. 3H). <br><br> Intermediate 58 <br><br> 2-[5-methyl-2-(4-pyridyi)-thiazol-4-yl}ethanol <br><br> 10 The title compound was prepared from 620 mg (2.50 mmol) of Intermediate 57 according to the method of Intermediate 43 followed by purification via silica gel flash column chromatography using a gradient of EtOAc to EtOAc a MeOH 30 /1 as eluent: 1H NMR (CDCI3l 400 MHz) 6 8.66 (d, 2H, J = 6.1), 7.71 (d. 2H, J = 6.1), 4.01 (m, 2H), 3.57 (t, 1H. J = 6.0), 2.93 (t, 2H, J= 5.8), 2.46 (s, 3H). <br><br> 15 <br><br> Intermediate 59 <br><br> 2(S)-{2-benzoyl-phenylamino)-3-{4-{2-{5-methyl-2-&lt;4-pyridyl)-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester <br><br> The title compound was prepared from 255 mg (0.68 mmol) of Intermediate 23 and 20 150 mg (0.68 mmol) of Intermediate 58 according to the method of Intermediate 44 followed by purification via silica gel flash column chromatography using hexane / EtOAc 3 / 2 as eluent: Anal. (C34H31N304S) Calcd. C, 70.69; H, 5.41; N, 7.27, Found C, 70.44; H, 5.50; N, 7.03. <br><br> 25 intornwdfrte 6p <br><br> [2-(2-dimethylamino)-5-methyl*thiazol-4-yl]-acetic acid methyl ester <br><br> A mixture of 750 mg (7.20 mmol, 1.5 equiv) of N.N-dimethyHhiiourea and 1.00 g (4.80 mmol) of methyl 4-bromo-3-o&gt;o-pentanoate in 10 mL of dioxane was heated to reflux for 3 h. The reaction was cooled to RT, diluted with 20 mL of EtOAc, anc: 30 washed with NaHC03 (1x10 mL). The organic layer was separated, dried (MgS04), and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using a gradient of hexane / EtOAc 1 / 5 to EtOAc / MeOH 20 / 1 as eluent afforded 210 mg of the title compound as an yellow oil: low resolution MS (FAB)m/e 216 (MH ), 215 (M+). <br><br> 35 <br><br> Printed from Mimosa <br><br> WO 97/31907 PCT/EP97/00916 <br><br> 53 <br><br> Intermediate 61 <br><br> 2-[2-dimethylamino-5-methyl-oxazol-4-yl]-ethanol <br><br> The title compound was prepared from 210 mg (0.98 mmol) of Intermediate 60 according to the method of Intermediate 43: low resolution MS (FAB)m / e 188 5 (MH+), 187 (M+). <br><br> Intermediate 62 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-{2-{2-dimethylamino-5-methyMhiazol-4-yl)-ethoxy]-phenyl)-propionic acid methyl ester <br><br> 10 The title compound (168 mg) was prepared from 390 mg (1.00 mmol) of Intermediate 23 and 185 mg (1.00 mmol) of Intermediate 61 according to the method of Intermediate 44 followed by purification via silica gel flash column chromatography initially using hexane / EtOAc 2 /1 as eluent to remove nonpolar impurities then using chloroform / MeOH to elute the desired product: low resolution 15 MS(FAB)m/e 544 (M ). <br><br> Intermediate 63 <br><br> 54Methylisoxazole*3-thiocarboxamide <br><br> A suspension of 525 mg (4.16 mmol) of 5-methylisoxazole-3-carboxamide and 1.85 20 g (4.58 mmol, 1.1 equiv) of Lawesson's reagent in 15 mL of dry toluene was heated to reflux for 5 h, during which time the reaction mixture became a clear yellow color. The reaction mixture was cooled to RT and the solvent was removed in vacuo. Purification of the material by silica gel flash column chromatography using a gradient of hexane / EtOAc 5 / 1 to hexane / EtOAc 1 / 1 as eluent followed by 25 trituration with acetonitrile, filtration to remove the solid Lawesson's reagent byproducts and removal of solvent afforded 614 mg of the title compound as a yellow oil: *H NMR (CDCI3, 300 MHz) 8 8.05 (s, br, 2H). 6.52 (s, 1H). 2.46 (s. 3H). <br><br> Intermediate 64 <br><br> 30 2-[5-methyl-2-(5-methyl-isoxazol-3-yl)-oxazol-4-yl]-acetic acid methyl ester <br><br> The title compound (375 mg) was prepared from 591 mg (4.15 mmol) of intermediate 63 and 950 mg (4.47 mmol, 1.10 equiv) of methyl 4-bromo-3-oxo-pentanoate according to the method of Intermediate 45 followed by purification via silica gel flash column chromatography using hexane / EtOAc 5 /1 as eluent: low 35 resolution MS (FAB)m / e 216 (MH+), 215 (M*). <br><br> Printed from Mimosa <br><br> WO 97/31907 PCT/EP97/D0916 <br><br> 54 <br><br> Intermediate 65 <br><br> 2-[5-fnethyl-2-(5-methyl-isoxazol-3-yl)-oxazoi-4-yl]-ethanol <br><br> The title compound (187 mg) was prepared from 375 mg (1.49 mmol) of 5 Intermediate 64 according to the method of Intermediate 43: 1H NMR (CDC^, 400 MHz) 8 6.50 (s. 1H), 3.97 (m, 2H), 3.46 (t, 1H, J = 6.2), 2.92 (t, 2H, J= 5.6), 2.49 (s, 3H). 2.44 (s, 3H). <br><br> Intermediate 66 <br><br> 10 2(S)-{2-benzoyl-phenylamino)-3-{4-[2-{5-methyi-2-(5-methyl-isoxazol-3-yl)-thiazol-4-yl)~ethoxy]-phenyl}-propionic acid methyl ester <br><br> The title compound (470 mg) was prepared from 530 mg (1.45 mmol) of Intermediate 23 and 317 mg (1.45 mmol) of Intermediate 65 according to the method of Intermediate 44 followed by purification via silica gel flash column 15 chromatography using a gradient of hexane / EtOAc 4 /1 to hexane / EtOAc 2 /1 as eluent: low resolution MS (FAB)m/e 582 (MH*). <br><br> Intermediate 67 <br><br> [5-methyl-2-{4'methyl[1,2l3]thiadiazol-5-yl)-oxazol-4-yl]*acetic acid methyl ester <br><br> 20 The title cornrjound (560 mg) was prepared from 1.0 g (7.00 mmol) of 4-methyl-1,2,3-thiadiazole-5-carboxamide and 2.97 g (7.35 mmol, 1.05 equiv) of Lawesson's reagent according to the method of Intermediate 63, followed by the procedure outlined for the preparation of Intermediate 45 and purification via silica gel flash column chromatography using hexane / EtOAc 4 / 1 as eluent: low resolution MS 25 (FAB)m/e 270 (M*). <br><br> Intermediate 68 <br><br> 2-{5-methyl-2-(4-methyl[1,2&gt;3]thi*diazol-5-yl)-oxazol~4-yl)-«thanol <br><br> The title compound (350 mg) was prepared from 560 mg (2.08 mmol) of 30 Intermediate 67 according to the method of Intermediate 43 followed by purification via silica gel flash column chromatography using chloroform / MeOH 9 /1 as eluent: 'h NMR (CDCI3, 400 MHz) 5 3.99 (m, 2H), 3.02 (s, br, 1H), 2.94 (m, 5H), 2.49 (s, 3H). <br><br> 35 Intermediate 69 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 55 <br><br> 2(S)-(2-b«nzoyl-pheny!»mino)-3-(4-{2-[5-methyl-2-(4-methyl[1,2I3]thiadi«zol-5-yl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid <br><br> The title compound (235 mg) was prepared from 560 mg (1.49 mmol) of Intermediate 23 and 360 mg (1.49 mmol) of Intermediate 68 according to the 5 method of Intermediate 44 followed by purification via silica gel flash column chromatography using a gradient of hexane! EtOAc 4 /1 to hexane / EtOAc 3 /1 as eluent: 1H NMR (CDCI3, 400 MHz) 6 8.88 (d. 1H. J = 7 3). 7.59 (dd, 2H, J= 1.6, 8.4) 7.48 (m, 3H), 7.33 (dd, 1H, J = 7.3, 7.3), 7.17 (d, 2H, J = 8.5), 6.80 (d, 2H, J = 8.5), 6.62 (d, 1H, J = 8.6). 6.58 (dd. 1H, J = 7.6, 7.6). 4.38 (m. 1H), 4.25 (t, 2H. J = 6.5), 10 3.69 (s. 3H), 3.16 (m, 4H). 2.92 (s, 3H), 2.50 (s, 3H). <br><br> Intermediate 70 <br><br> [5-methyl-2-(4-methyl-piperazin-1-yl)-thiazoM-y!]-acetic acid methyl ester <br><br> The title compound (490 mg) was prepared from 18.7 g (104.8 mmol) of 15 thiocarbonyldiimidazole and 10 g (99.8 mmol) of 1 methyl piperazine according to the method of Intermediate 53, followed by the procedure outlined for the preparation of Intermediate 60 and purification via silica gel chromatography using MeOH/EtOAc (3:17) as eluent: TLC (MeOH/EtOAc (1:9)): Rt = 0.15. <br><br> 20 Intermediate 71 <br><br> 2-{&amp;-methy!-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-«thanol <br><br> The title compound (2.20 g) was prepared from 2.87 g (8.10 mmol) of Intermediate 70 according to the method of Intermediate 43 followed by purification via silica gel flash column chromatography using chloroform / MeOH 10 M as eluent: H NMR 25 (CDCI3, 400 MHz) 5 4.42 (s. br. 1H). 3.85 (m, 2H). 3.41 (m, 4H), 2.67 (t. 2H, J = 5.4), 2.49 (m, 4H), 2.34 (s. 3H), 2.20 (s, 3H). <br><br> Intermediate 72 <br><br> [2-(3-dimethylamino-propylamino)-5-methyl-th;azol-4-yl]-acetic acid methyl 30 ester <br><br> The title compound (854 mg) was prepared from 1.0 g (6.20 mmol) of 3-dimethylaminopropyl thiourea and 1.30 g (6.20 mmol) of methyl 4-bromo-3-oxo-pentanoate according to the method of Intermediate 45: low resolution MS (FAB)m / e 272 (M+). <br><br> 35 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 56 <br><br> Intermediate 73 <br><br> 2-{2-{3-dimethylamino-propylamino)-5-methyl-thiazol-4-yl]-ethanol <br><br> The title compound (606 mg) was prepared from 850 mg (3.14 mmol) of Intermediate 72 according to the method of Intermediate 43: 1H NMR (COCI3. 400 5 MHz) d 6.18 (s, br, 1H), 4.40 (s, br. 1H), 3.83 (t. 2H, J = 5.5), 3.28 (m, 2H), 2.65 (t, 2H, 5.5). 2.39 (t. 2H, J= 6.4), 2.23 (s, 6H), 2.18 (s, 3H), 1.76 (m, 2H). <br><br> Intermediate 74 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-{2-[2-(3-dimethylamino-propylamino)-5-10 methy!-thiazol-4-yl]-«thoxy)-phenyl)-propionic acid methyl eeter <br><br> A suspension of 715 mg (2.73 mmol, 1.10 equiv) of triphenylphosphine, 929 mg (2.48 mmol) of Intermediate 23, and 600 mg (2.48 mmol) of Intermediate 73 in 25 mL of dry toluene was heated to 95 °C for 15 min to effect dissolution of Intermediate 23 to provide a clear yellow solution. To this solution was added 452 15 mg (2.60 mmol, 1.05 equiv) of diethyl azodicarboxylate dropwise over 5 min. The reaction was then allowed to cool to RT and stirred 16 h. The toluene was removed in vacuo, and the residue was purified by silica gel flash column chromatography using EtOAc / MeOH 1/1 with 1% ammonium hydroxide as eluent to afford 770 mg <br><br> ♦ <br><br> of the title compound as a yellow oil: low resolution MS (FAB)m/e 602 (MH ), 601 20 (M*). <br><br> Intermediate 75 <br><br> 2-[2-(2-methoxy-ethylamino)-5-methyl-thiazol~4-yl]-ethanol <br><br> The title compound (800 mg) was prepared from 750 mg (5.59 mmol) of 2-25 methoxyethyl thiourea and 1.17 g (5.59 mmol) of methyl 4-bromo-3-oxo-pentanoate according to the method of Intermediate 60, followed by the procedure outlined for the preparation of Intermediate 43 nd purification via silica gel flash column chromatography using chloroform / MeOH 9 / 1 as eluent: H NMR (CDCI3&gt; 400 MHz) 8 3.82 (t, 2H, J = 5.5), 3.58 (t, 2H. J = 6.9), 3.41 (m, 2H). 3.36 (s, 3H), 2.65 (t, 30 2H, J = 6.9), 2.19 (s, 3H). <br><br> Intermediate 76 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[2-(2-methoxy-ethy,imino)-5-m»thyl-thiazol-4-yl]-ethoxy)-phenyl)-propionic acid methyl ester <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/639I6 <br><br> 57 <br><br> The title compound (907 mg) was prepared from 1.38 g (3.70 mmol) of Intermediate 23, and 800 mg (3.70 mmol) of Intermediate 75 according to the method of Intermediate 74 followed by purification via MPLC (Merck Lobar Si60 column, diethyl ether / dichloromethane 1 / 4 as eluent): low resolution MS (FAB)m/e 574 (M ). <br><br> 5 <br><br> Intermediate 77 <br><br> 3-{4-[2-(Benzoxazol-2-yl-m®thyl-amino)-ethoxy]-phenyl}~2-(2-cyclopentanecarbonyl~phenylamino)-proplonic acid methyl ester <br><br> The title compound (580 mg) was prepared from 650 mg (1.71 mmol) of 10 Intermediate 9, 646 mg (3.42 mmol, 2.0 equiv.) of (2-amino-phenyl)-cyclopentyl-methanone and 15 mg (0.003 mmol, 0.01 equiv.) of rhodium acetate according to the method of Intermediate 3 followed by purification via silica gel flash column chromatography using hexane / EtOAc 7 / 3 as eluent: low resolution MS (ES) m/e 542.1 (MH*). <br><br> 15 <br><br> Intermediate 78 <br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-cycloheptanecarbonyl-phenylamino)-propionic acid methyl aster <br><br> The title compound (130 mg) was prepared from 650 mg (1.71 mmol) of 20 Intermediate 9, 742 mg (3.42 mmol, 2.0 equiv.) of (2-amino-phenyl)-cycloheptyl-methanone and 15 mg of rhodium acetate according to the method of Intermediate 3 followed by purification via silica gel flash column chromatography using hexane / EtOAc 7 / 3 as eluent: low resolution MS (ES) m/e 569.9 (MH*). <br><br> 25 Intermediate 79 <br><br> 3-{4-[2-(B®nzoxazol-2-yl-m®thyl-amino)-ethoxy]-ph®nyl}-2-(2-cyclohoxanecarbonyl-5-fluoro-phenylamino)-proplonic acid methyl ester <br><br> The title compound (392 mg) was prepared from 400 mg (1.71 mmol) of Intermediate 9, 325 mg (1.47 mmol, 1.4 equiv.) of (2-amino-4-fluoro-phenyl)-30 cycloheptyl-methanone and 10 mg of rhodium acetate according to the method of Intermediate 3 followed by purification via silica gel flash column chromatography using hexane / EtOAc 7 / 3 as eluent: low resolution MS (ES) m/e 574.0 (MH ). <br><br> Intermediate 80 <br><br> Printed from Mimosa <br><br> WO 97/31907 PCT/EP97/00916 <br><br> 58 <br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-«thoxy]-phenyl}-2-(4-cyclohexane carbonyl-2-methyl-2H-pyrazol-3-ylamino)-propionic acid methyl ester <br><br> The title compound (278 mg) was prepared from 400 mg (1.05 mmol) of Intermediate 9, 287 mg (1.47 mmol, 1.4 equiv.) of (5-amino-1-methyl-lH-pyrazol-4-5 yl-cyclohexyl-methanone and 10 mg of rhodium acetate according to the method of Intermediate 3 followed by purification via silica gel flash column chromatography using hexane / EtOAc 7 / 3 as eluent: low resolution MS (ES) m/e 560.2 (MH ). <br><br> Intermediate 81 <br><br> 10 3-{4-[2-(Benzoxazol-2-yl-m«thy l-amino)-ethoxy]-phenyl}-2-(3-benzoyl-thiophene-2-ylamlno)-propionlc acid methyl ester <br><br> The title compound (145 mg) was prepared from 137 mg (0.36 mmol) of Intermediate 9 , 104 mg (0.51 mmol, 1.4 equiv.) of (2-amino-thiophen-3-yl)-phenyl-methanone and 5 mg of rhodium acetate according to the method of Intermediate 3 15 followed by purification via silica gel flash column chromatography using hexane / EtOAc 7 / 3 as eluent: low resolution MS (ES) m/e 556.0 (MH*). <br><br> interme4'«t» 83 <br><br> 2-(2-Cyclohexan«carbonyl-ph«nylamino)-3-{4-[2-{5-methyl-2-ph«nyl-oxazol-4-20 yl)-ethoxy]-phenyl)-propionic acid methyl ester <br><br> The title compound (2.89 g) was prepared from 3.03 g (7.75 mmol) of Intermediate 121, 2.07 g (10.51 mmol, 1.4 equiv.) of (2-amino-phenyl)-cyciohexyl-methanone and 69 mg of rhodium acetate according to the method of Intermediate 3 followed by purification via silica gel flash column chromatography using DCM to 1/99 diethyl 25 ether/DCM as eluent: low resolution MS (ES) m/e 567.4 (MH ), The enantiomers of this material were then separated on a Prep OO Column ; Enantiomer 1: NMR, MS, HPLC identical to racemate. Enantiomer 2: NMR, MS.HPLC identical to racemate. <br><br> Intermediate 84 30 (S)(-)-1-benzyl-pyrrolidin-3-yl methanesulfonate <br><br> To (S)(-&gt;-1 -benzyl-3-pyrrolidinol (5 g. 28.2 mmol) in pyridine (40 mL) was added methane sulphonyl chloride (2.03 mL, 26.2 mmol, 0.93 equiv.) dropwise. The reaction mixture stirred 3h, was poured into ice water (100 mL) and extracted with DCM (3 X 50 mL). The combined organic extracts were washed with saturated aq <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/009I6 <br><br> 59 <br><br> NaHC03, brine and dried (MgS04) to give 3 g of the titled compound: low resolution MS (ES) m/e 256.0 (MH*). <br><br> Intermediate 85 <br><br> 5 2-{2-Benzolyl-phenyl«mino)-3-[4-(1-benzyl-pyrrolidin-3-yioxy)-ph®nyl]-propionic acid methyl ester <br><br> To a stirring solution of 1.0 g (2.66 mmol) of Intermediate 23 in 30 mL of DMF was added 0.95 g (2.95 mmoi, 1.1 equiv.) of cesium carbonate and 747 mg. (2.93 mmol, 1.1 equiv.) of Intermediate 84. The resulting solution was stirred 24b at 45 C then 10 quenched into 10 mL water. The reaction mixture was poured into 25 mL of EtOAc and 25 mL of Et20 and extracted with HzO (3X10 mL). The organic layer was dried (MgS04), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane / EtOAc 7 / 3 as eluent afforded 0.68 g of the title compound: low resolution MS (API) m/e 535.1 (MH ). <br><br> 15 <br><br> Intermediate 86 <br><br> 3-{4-&lt;1-Benzoxazol-2-yl-pyrrolldin-3-yloxy)-phenyl]-2-{2-benzoyl-ph«nyl«mino)-propionic acid methyl ester <br><br> To 0.60 g of Intermediate 85 (1.12 mmol) in DCM (30 mL) at 0°C was added alpha-20 chloroethy! chioroformate (0.24 mL, 2.24 mmol, 2 equiv). The reaction mixture stirred at 0°C for 30 min and then was concentrated to dryness. The resulting residua was dissolved in MeOH (100 mL), refluxed for 2.5h, then concentrated to dryness. To this crude material (0.71 g, 1.12 mmol) was added triethylamine (0.47 mL, 3.36 mmol, 3 equiv). The reaction mixture stirred 5 min followed by dropwise 25 addition of 2-chloro-benzoxazole in THF (2 mL). The reaction mixture stirred 12h at RT, was concentrated in vacuo. Purification by silica gel flash column chromatography using ET20/ DCM 10/ 90 as eluent afforded 200 mg of the titled product: low resolution MS (ES) m/e 562.1 (MH*). <br><br> 30 Intermediate 87 <br><br> 3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-®thcxy]-phenyl}-2(S)-[2-(pyridine-4-carbonyl)-phenylamino]-propionlc acid methyl ester <br><br> The title compound (2.92 g) was prepared from Intermediate 120 (3.65 g, 9.61 mmol) and 2-(pyridine-4-carbonyl)-cyclohexanone (2.92 g, 9.61 mmol) according to 35 the method of Intermediate 23 followed by purification via silica gel flash column <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 60 <br><br> chromatography using DCM /MeOH 98 /2 as eluent: low resolution MS (ES) m/e 546.0 (MH*). <br><br> Intermediate 88 <br><br> 5 3-{4-[2-&lt;5-methyl-2-ph0nyl-oxazol-4-yl)-ethoxy]-phenyl}-2-[2-(pyridlneN-oxlr?e-4-carbonyl)-phenylamino]-propionic acid methyl ester <br><br> To Intermediate 87 (200 mg, 0.36 mmol) in DCM (5 mL) at RT was added mCPBA (185 mg, 1.07 mmol, 3 equiv). After 24h the reaction mixture was concentrated in vacuo. Purification by silica gel flash column chromatography using DCM / MeOH 10 98 / 2 to 90 /10 as eluent afforded 90 mg of the title compound: low resolution MS (ES) m/e 578 1 (MH*). <br><br> intermediate 89 <br><br> 3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-«thoxy]-ph*nyl}-2(S)-[2-(pyridine-3-15 carbonyl)-pheny!amino]-propionic acid methyl ester <br><br> The title compound (540 mg) was prepared from Intermediate 120 (1.30 g. 2.63 mmol) and 2-(pyridine-3-carbonyl)-cyclohexanone (1.07 g, 5.26 mmol) according to the method of Intermediate 23 followed by purification via silica gel flash column chromatography using hexane to 1/1 hexane/ EtOAc as eluent: low resolution MS 20 (ES) m/e 562.2 (MH*). <br><br> Intermediate 90 <br><br> 2-(5-methyl-3-phenyl-pyrazol-1 -yl)-ethanol <br><br> A solution of 497 mg (3.14 mmol) of 3-methyl-5-phenylpyrazole in 12.6 mL of DMF 25 at 0°C was treated with 138 mg (3.45 mmol, 60% in oil) of NaH. After stirring for 15 min, 1.38 g (15.7 mmol) of ethylene carbonate was added, and the reaction was wanned to 25"C and stirred overnight. The reaction was diluted with H20 and the product was extracted with hexanes/EtOAc (1:1). The combined organics were dried (MgS04), filtered, and concentrated in vacuo. The residue was purified by 30 silica gel flash column chromatography using hexanes/EtOAc (1:3) as eluent to give 305 mg (48%) of title compound: low resolution MS (ES) m/e 225 (MNa), 203 (MH*). <br><br> intermediate 91 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 61 <br><br> 2S-(2-benzoyl-phenyiamino)-3-{4-[2-(5-methyl-3-phenyl-pyrazol-1-yl)-ethoxy}-phenyl}-propionic acid methyl ester <br><br> A solution of 169 mg (0.45 mmol) of Intermediate 23, 100 mg (0.49 mmol) of Intermediate 90, and 177 mg (0.67 mmol) of triphenylphosphine in 4.5 mL of THF at 5 25°C was treated dropwise with 0.106 mL (0.67 mmol) of DEAD. The reaction was stirred at 25°C for 24 h then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexanes/EtOAc (2:1) as eluent to give 116 mg (46%) of title compound as a viscous yellow oil: low resolution MS (ES) m/e 582 (MNa*), 560 (MH*). <br><br> 10 <br><br> intermediate 92 <br><br> 2S-(2-b«nroyl-phenylamino)-3-{4-(1-tert-butoxycarbonyl-pyrrolidin-2S-yl-methoxy)-phenyl]-propionic acid methyl ester <br><br> The title compound (1 62 g) was prepared from 2.82 g (7.5 mmol) of Intermediate 23 15 and 1.66 g (8.25 mmol) of N-tert-butoxycarbonyl-L-prolinol according to the method of Intermediate 91 followed by purification via silica gel flash column chromatography eluting with hexanes/EtOAc (3:1) as eluent: low resolution MS (ES) m/e 581 (MNa*), 559 (MH*). <br><br> 20 Intermediate 93 <br><br> 2S-(2-benzoyl-phenylaminc)-3-[4-{1~pyridin-2-yl-pyrrolidin-2S-yl-methcxy)-phenyl]-propiontc acid methyl ester <br><br> A solution of 2.95 g (5.3 mmol) of Intermediate 92 in 62 mL of CH2CI2 was treated with 62 mL of trifluoroacetic acid and stirred 1 h. The reaction was diluted with 25 CH2CI2 and basified with saturated Na2C03. The aqueous layer was extracted with CH2CI2i and the combined organic layers were dried (Na2S04), filtered, and concentrated in vacuo. The residue was dissolved in 210 mL of 2-fluoropyridine and heated at reflux for 24 h. Upon cooling to 25°C the reaction was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography 30 eluting with hexanes/EtOAc (2:1) to give 1.2 g (42%) of the title compound as a viscous yellow oil: low resolution MS (ES) m/e 558 (MNa ), 536 (MH ). <br><br> Intermediate 94 <br><br> 2-( 1 -methyl-4-pheny 1-1 H-imidazol-2-yl)-ethanol <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 62 <br><br> A solution of 674 mg (4.26 mmol) of 1-methyl-4-phenylimidazole (Kashima, C.; Harada, Y.; Hosomi, A. Heterocycles 1993, 35, 433) in 8.5 mL of THF at -78°C was treated with 1.9 mL (4.69 mmol) of a 2.5 M nBuLi in hexanes solution. After stirring for 10 min, 1.1 mL (21.3 mmol) of ethylene oxide was added. The reaction was 5 stirred for 5 min then warmed to 25°C and stirred for 1 h. Upon cooling to 0°C, 1.1 mL (21.3 mmol) of ethylene oxide was added, and the reaction was warmed to 25°C and stirred overnight. The reaction was poured into H20 and extracted with Et^. The combined organics were dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using 10 EtOAc/MeOH (95:5), and the collected product was recrystaliized from CH2Cl2/EtOAc to give 178 mg (21%) of title compound as a white solid: low resolution MS (ES) m/e 225 (MNa ), 203 (MH*). <br><br> Intermediate 95 <br><br> 15 2S-(2*benzoyH&gt;h«nylaminol-3-{4-[2-(1 -methy l-4-pheny 1*1 H-imidazol-2-yl)-ethoxy]*phenyl}-propion!c acid methyl ester <br><br> The title compound (90 mg) was prepared from 93 mg (0.25 mmol) of Intermediate 23 and 50 mg (0.25 mmol) of Intermediate 94 according to the method of Intermediate 91 followed by purification via silica gel flash column chromatography 20 using hexanes/EtOAc (1:3) as eluent: low resolution MS (ES) m/e 582 (MNa ), 560 (MH*). <br><br> Intermediate 96 3-furan-2-yl-5-methylpyrazole <br><br> 25 To a solution of 1.07 g (7.03 mmol) of 1-(2-furyl)-1,3-butanedione in 26 mL of MeOH at 25°C was added 0.442 mL (14.07 mmol) of hydrazine. The reaction was stirred for 24 h then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexanes/EtOAc (1:1) as eluent to give 1.02 g (98%) of title compound: low resolution MS (CI) m/e 149 (MH ). <br><br> 30 <br><br> Intermediate 97 <br><br> 2-(3-furan-2-yl-5-methyl-pyrazol-1-yl)-ethanol <br><br> The title compound (189 mg) was prepared from 1.01 g (6.82 mmol) of Intermediate 96 according to the method of Intermediate 90 followed by purification via silica gel <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/009I6 <br><br> 63 <br><br> flash column chromatography using hexanes/EtOAc (1:3) as eluent low resolution MS (CI) m/e 215 (MNa*), 193 (MH*). <br><br> Intermediate 98 5 2-(5-methy l-3-phenyl-[1,2,4]triazol-1 -yl)-ethanol <br><br> The title compound (140 mg) was prepared from 550 mg (3.45 mmol) of 3-phenyt-5-methyHI ,2.4]triazole (Francis, J. E.; Gorczyca, L. A.; Mazzenga, G. C.; Meckler, H. Tetrahedron Lett. 1987, 28, 5133) according to the method of Intermediate 90 followed by purification via silica gel flash column chromatography using 10 EtOAc/MeOH (95:5) as eluent and recrystallization from Et20: low resolution MS (CI) m/e 204 (MH*). <br><br> Intermediate 99 <br><br> 2S-{2-benzoyl-phenyl«mino)-3-{4-{2-(5-methyl-3-phenyl-[1,2,4ltriazol-1-yl)-15 ethoxy]-phenyl}*propionic acid methyl ester <br><br> The title compound (186 mg) was prepared from 196 mg (0.52 mmol) of Intermediate 23 and 106 mg (0.52 mmol) of Intermediate 98 according to the method of Intermediate 44 followed by purification via silica gel flash column chromatography using hexanes/EtOAc (1:1 /E 1:2) as eluent: low resolution MS (ES) 20 m/e 583 (MNa*), 561 (MH*). <br><br> Intermediate 100 <br><br> 3-methoxymethyl-5-methyl-2-phenyl-3H-imidazole <br><br> To a solution of 1.0 g (6.32 mmol) of 4-methyl-2-phenyiimidazole in 25 mL of OMF at 25 0*C was added 278 mg (6.95 mmol, 60% in oil) of NaH. After stirring for 5 min, 0.528 mL (6.95 mmol) of chloromethyl methyl ether was added, and the reaction was warmed to 25"C and stirred 4 h. The reaction was poured into H20, and the product was extracted with hexanes/EtOAc (1:1). The combined organic layers were dried (Na2S04), filtered, and concentrated in vacuo. Purification by silica gel 30 flash column chromatography using hexanes/EtOAc (5:95) as eluent provided 816 mg (64%) of title compound: low resolution MS (ES) m/e 225 (MNa ), 203 (MH*). <br><br> Intermediate 101 <br><br> 2-(3-methoxymethyl-5-methyl-2-phenyl-3H-imidazol-4-yl)-ethanol <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 64 <br><br> The title compound (433 mg) was prepared from 710 mg (3.51 mmol) of Intermediate 100 according to the method of Intermediate 94 followed by purification via silica gel flash column chromatography using EtOAc/MeOH (93:7) as eluent: low resolution MS (ES) m/e 269 (MNa*), 247 (MH*). <br><br> 5 <br><br> Intermediate 102 <br><br> 2S-{2-benzoyl-phenylamino)-3-(4-{2-(3-methoxymethyl-5-methyl-2-phenyl-3H-imidazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester <br><br> The title compound (347 mg) was prepared from 314 mg (0.84 mmol) of 10 Intermediate 23 and 207 mg (0.84 mmol) of Intermediate 101 according to the method of Intermediate 44 followed by purification via silica gel flash column chromatography using EtOAc/hexanes (3:1) as eluent to give 347 mg (69%) of title compound: low resolution MS (ES) m/e 604 (MNa*), 626 (MH ). <br><br> 15 intermediate 103 <br><br> 2-(3-trimethyisilylethoxymethyl-5-methyl-2-phenyl-3H'imidazol-4-yl)-ethanol <br><br> A solution of 1.04 g (6.57 mmol) of 2-phenyl-3-methy!imidazole in 25 mL of DMF at 0*C was treated with 289 mg (7.23 mmol, 60% in oil) of NaH. After stirring for 5 min, 1.28 mL (7.23 mmol) of 2-(trimethylsilyl)ethoxymethyl chloride was added. The 20 reaction was stirred for 10 min then warmed to 25"C and stirred overnight. The reaction was poured into H20, and the product was extracted with hexanes/EtOAc (1:1). The combined organic layers were dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using EtOAc/MeOH (98:2) as eluent to give 1.18 g (62%) of protected intermediate. This 25 material was then converted to the title compound (851 mg) according to the method of Intermediate 94 followed by purification via silica gel flash column chromatography using EtOAc/MeOH (95:5 /E 9:1) as eluent: low resolution MS (ES) m/e 233 (MH*). <br><br> 30 Intermediate 104 <br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2«(5-methyl-2-phenyl-3H-imidazol-4-yl)-ethoxy]-phenyl)-propionic acid methyl ester <br><br> The title compound (542 mg) was prepared from 931 mg (2.48 mmol) of Intermediate 23 and 825 mg (2.48 mmol) of intermediate 103 according to the 35 method of Intermediate 44 followed by purification via silica gel flash column <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 65 <br><br> chromatography using hexanes/EtOAc (2:1 /E 1:1) as eluent to give 867 mg of impure intermediate. A solution of 830 mg (1.2 mmol) this material in 12 mL of CH3CN at 0°C was treated with 0.222 mL (1.8 mmol) of BF3*OEt2. After stirring for 30 min at 0"C then at 25°C for 1 h, an additional 0.444 mL (3.6 mmol) of 8F3«OEt2 5 was added. After stirring for a further 1 h, an additional 0.444 mL (3.6 mmol) of BF3*OEt2 was added and stirring was continued for 35 min. The reaction was poured into saturated NaHC03, and the product was extracted with EtOAc. The combined organic layers were dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using 10 hexanes/EtOAc (1:1) as eluent: low resolution MS (ES) m/e 560 (MH ). <br><br> Intermediate 105 <br><br> 5-methyl-2-phenyl-4-thiazoleacetic acid methyl ester <br><br> The title compound (827 mg) was prepared from 1.0 g (4.78 mmol) of methyl 4-15 bromo-3-oxo-pentanoate and 2.6 g (19.14 mmol) of thiobenzamide according to the method of Intermediate 42 followed by purification via silica gel flash column chromatography using hexanes/EtOAc (3:1) as eluent: low resolution MS (ES) m/e 270 (MNa*), 248 (MH*). <br><br> 20 Intermediate 106 <br><br> 2-(6-methyl-2-phenyl-thlazol-4-yl)-ethanol <br><br> The title compound (52? mg) was prepared from 817 mg (3.30 mmol) of Intermediate 105 according to the method of Intermediate 43 followed by purification via silica gel flash column chromatography using hexanes/EtOAc (1:2) as eluent: low 25 resolution MS (ES) m/e 242 (MNa*), 219 (MH*). <br><br> Intermediate 107 <br><br> 2S-(2-benzoyl-phenylamino)-3-(4-[2-{5-methyl-2-phenyl-thiazol-4-yl)-ethoxy)-phenyl}-propionic acid methyl ester <br><br> 30 The title compound (378 mg) was prepared from 348 mg (0.93 mmol) of Intermediate 23 and 203 mg (0.93 mmol) of Intermediate 106 according to the method of Intermediate 43 followed by purification via silica gel flash column chromatography using hexanes/EtOAc (3:1) as eluent: low resolution MS (ES) m/e 599 (MNa*), 577 (MH*). <br><br> 35 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 66 <br><br> Intomndiate 108 <br><br> Methyl 3 -&lt;5 -mathyl-2-thionylamino)-4-oxopentanoate <br><br> A slurry of 19.3 g (0.136 mol) 5-methyl-2-thiophenecarboxylic acid in 200 mL of toluene was treated with 10.9 mL (0.15 mol) of thionyl chloride. The resulting mixture 5 was heated to 70 "C for 16 h, then concentrated in vacuo. The resulting oil was added in portions to a solution of 25.0 g (0.136 mol) of b-methylaspartic acid hydrochloride in 80 mL of pyridine at 0 "C at a rate to maintain a temperature &lt;10 °C. After the addition was complete the solution was allowed to stir at 25 °C for 1 h, treated with 50 mL of acetic anhydride and heated to 90 °C for 2 h. The mixture was 10 then cooled to 25 °C, poured into 700 mL of 1N HCI, and extracted three times with EtOAc. The combined organic phases were washed three times with 3 N HCI. once with water, once with 5 % Aq NaHC03, and finally with brine. The solution was dried (Na2S04), then chromatographed over silica gel eluting with hexanesrEtOAc 3/12 to obtain 9.1 g (25 %) of the title compound as a clear yellow oil: MS (ES+) m/e 270 15 (MH+). <br><br> Intermediate 109 <br><br> (5-m8thyl-2-{5-fTiethyl-2-thienyl)-oxazo-4-yl) acetic acid methyl ester <br><br> A solution of 3.97 g (14.7 mmol) of Intermediate 108 in 100 mL of anhydrous 20 acetonitrile was treated with 4.1 mL (44.2 mmol) of phosphorous oxychloride and heated to reflux for 5 h. The solution was cooled to 25 °C and a dark oil was decanted from the tar at the bottom of the flask. The solution was concentrated in vacuo and diluted with water and EtOAc. The aqueous layer was saturated wi" KHC03, the Isvcs were separated and the solution was extracted twice more witr. 25 EtOAc. The r.&gt;'rained organic phases were dried (Na2S04) and concentrated in vacuo to givs orange oil. which was chromatographed over silica gel eluting with dichloromethane:EtOAc 20/1. The residue after concentration in vacuo was rechromatographed over silica gel eluting with hexane:EtOAc 2 /1 to obtain 2.94 g (79 %) of the title compound as a pink-orange oil: MS (API+) m/e 252 (MH+). <br><br> 30 <br><br> Intermediate 110 <br><br> 2 -(5 -methyl-2-(5-methyl-2-thienyl)-oxazol-4-yl) ethanol <br><br> The title compound (1.05 g) was prepared from 2.94 g (11.7 mmol) of Intermediate 109 according to the method of Intermediate 43 followed by purification via silica gel 35 chromatography eluting with hexanes:EtOAc 1/1: MS (API+) m/e 224 (MH+). <br><br> Printed from Mimosa <br><br> WO 97/31907 PCT/EP97/00916 <br><br> 67 <br><br> Intermediate 111 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-5-methyl-2-(5-methy!-2-thienyl)-oxazol-4-yl)-athoxy]-r&gt;henyl)-propionic acid methyl ester <br><br> 5 The title compound (440 mg) was prepared from 700 mg (3.13 mmol) of Intermediate 110 and 1.18 g (3.13 mmol) of Intermediate 23 according to the method of Intermediate 44 followed by purification via silica gel chromatography eluting with toluene:EtOAc 20 / 1: MS (ES+) m/e 581 (MH+); TLC (PhMe:EtOAc/90:10): R, = 0.25. <br><br> 10 <br><br> Intermediate 112 <br><br> 2(S)-(2-benzoyl-phBnylamino)-3-{4-[2-(5-niethyl-2-(3-methyl-thien-2-yl)-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester <br><br> The title compound (100 mg) was prepared from 3.7 g of (5-methyl-2-(3- methyl-2-15 thienyi)-oxazo-4-yl) acetic acid methyl ester (prepared analogously to Intermediate 109) according to the method of Intermediate 43 followed by reaction with 375 mg (1.0 mmol) of Intermediate 23 according to the method of Intermediate 44, followed by purification via silica gel chromatography eluting with 95:5/toluene:EtOAc: MS (ES+) m/e 581 (MH+); TLC (PhMe:EtOAc/90:10): Rf = 0 38. <br><br> 20 <br><br> internwtftote 113 <br><br> 2-(2-iodo-phenyl)-3-{4-{2(b«nzoxazol-2-yl-methyl-amino)-«thoxy]-phenyl}-propionic acid methyl ester <br><br> To a solution of 2.88 g (13 ' *nmol) of 2-iodoaniline stirred in 50 mL of toluene 25 under a nitrogen atmosphere at 25 °C was added 26.3 mL of a 0.1 M solution of Intermediate 10 in toluene, followed by 58 mg (0.132 mmol) of rhodium (II) acetate dimer. The resulting solution was stirred for 16 h at 25 C, then concentrated in vacuo to a dark brown oil. The crude product was chromatographed over silica gel eluting with CH2CI2 to obtain 1.12 g (75 %) of the title compound. MS (API) m/e j73 30 (MH+), 572 (M+). <br><br> Intermediate 114 <br><br> 4(R)-Hydroxymethyl-thiazolidina-3-carboxylic acid tart-butyl ester <br><br> A solution of 4.66 g (20 mmoi) of N-Boc-thioproline and 3.84 mL (22 mmol) DIEA 35 dissolved in 10 mL THF was cooled to 0_C and treated with 2.1 mL (22 mmol) of <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/009J 6 <br><br> 68 <br><br> ethyl chloroformate. After 30 min at RT the white precipitate is filtered off, the solution cooled to 0 °C and a solution of 8.32 g (220 mmol) sodium borohydride in 30 mL H20 is added dropwise. The reaction was stirred for 24 h, then cooled to 0 "C and quenched by dropwise addition of acetic acid. The product was then extracted 5 with EtOAc, the combined organics were washed successively with sodium bicarbonate and citric acid, dried with magnesium sulfate filtered and solvents removed in vacuo to provide 2.33g of the title compound: MS (ES+) m/e 242 (M+23), 120 (M-Boc+1). <br><br> 10 Intermediate 115 <br><br> 4(R)-{4-{2(SH2-Benzoyl-phenylamino)-2-methoxycarbonyl-ethyl]-phanoxymethyl}-thiazolidlna-3-carboxylic acid tert-butyl aster <br><br> A solution of 1.20 g (5.48 mmol) of Intermediate 114, 2.05 g (5.48 mmol) of Intermediate 23 and 1.58 g (6.03 mmol) of the triphenylphosphine in 7 mL of THF 15 was dropwise added 0.95 mL (6.03 mmol) of DEAD at 0 °C. The reaction mixture was stirred at RT for 1 h, solvents removed in vacuo and the crude mixture purified via silica gel column chromatography using EtOAc/hexane 1/3 as eluent to afford 530 mg of the title compound: MS (ES-*-) m/e 599 (M+23). <br><br> 20 Intermediate 116 <br><br> 3-[4-{3-Benzoxazol-2-yl-thlazolidin-4{R)~ylm«thoxy)-phanyf]-2(S)-{2-benzoyl-phenylamlno)-proplonlc acid methyl ester <br><br> Intermediate 115 (500 mg, 0.868 mmol) was treated with 5 mL of 4N HCI in dioxane for 1.5 h. Solvents were then evaporated and the crude hydrochloride salt dissolved 25 in 20 mL dichloromethane. To this solution was added 767 mg (5.0 mmol) of chlorobenzoxazole and 1.29 g (10.0 mmol) of DIEA and allowed the resulting solution was stirred at RT for 36 h. The voiatiles were then removed in vacuo, and the solid residue purified by silica gel flash column chromatography using EtOAc/hexane 1:1 as eluent to afford 128 mg of the title compound: <br><br> 30 MS (ES+) m/e 594 (MH+). <br><br> Intermediate 117 <br><br> 2(S)-(2-Banzoyl-phenylamino)-3-(4-hydroxyphenyl)-propionic acid <br><br> The title compound (1.63 g) was prepared from 1.79 g (4.66 mmol) of Intermediate 35 23 according to the method of Example 32: MS (ES+) m/e 384 (MH+23). <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 69 <br><br> PCT/EP97/00916 <br><br> Intermediate 118 <br><br> 2(SH2-BenzoyUphenylamino)-3-(4-hydroxy-phenyi)-propionic acid (2-chloro-phenyl)-diphenyl-mathyl ester attached to polystyrene resin <br><br> 5 A solution of 1.63 g (4.4 mmol) of Intermediate 117 in 10 mL of MeOH and 5 mL of water was treated with 0.852 (4.4 mmol) of cesium bicarbonate. The solution was stirred for 10 min at RT, then solvents were removed and the resulting solid cesium salt dried in vacuo. A slurry of 480 mg of the CI-Trityl-polystyrene (PS) resin (substitution 1.5 mmol/g) in 4 mL of dry DMF was treated with 60 mg (~ 1mmol) of 10 the cesium salt described above and reacted for 20 h at f0 "C. Resin was then filtered off and washed successively 10x with DMF, 1:1 DMF / ethanol, ethanol and ethyl ether, resulting in 550 mg of the dry product. The substitution (0.49 mmol/g) of this derivatized resin was then calculated based on the combustion analysis (C(ouna 79.46%, H(eund 5.94%, 0.68%). <br><br> 15 <br><br> Intermediate 119 <br><br> 2(SHtert-butoxycarbonyl-amino)-3-(4-[2-{5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester <br><br> The title compound (15.9 g) was prepared from 15.0 g (73.8 mmol) of 2-(5-methyl-2-20 phenyll-oxazol-4-yl)-ethanol and 21.8 g (73.8 mmol) of 2(S)-(tert-butoxycarbony I-amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester according to the method of Intermediate 44 followed by purification via silica gel chromatography using diethyl ether/dichioromethane (1.19). low resolution MS (ES) m/e 481 (MH*). <br><br> 25 Intermediate 120 <br><br> 2(S)~amino-3-{4-{2-&lt;5-methyl-2-phenyl-oxazol-4-yl)&lt;«thoxy]-phenyl}-propionic acid methyl ester <br><br> To a stirred solution of 15.92 g (33.1 mmol) of Intermediate 119 in 300 mL of dichloromethane at RT was added 33 mL (10% volume) of trifluoroacetic acid. After 30 stirring 5 h. the reaction was quenched with 0.1 N NaOH and the layers separatee The organics were washed with water, the layers separated, the organics dried (MgSOJ, and the solvent remove in vacuo to give the title compound as the monotrifluoro acetate salt: low resolution MS (ES) m/e 381 (MH*). <br><br> 35 Intermediate 121 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 70 <br><br> 2-diazo-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-athoxy]-phenyl}-propionic acid methyl ester <br><br> The title compound (240 mg) was prepared from 500 mg (1.01 mmol) of Intermediate 120 according to the method of Intermediate 9 followed by purification 5 via silica gel chromatography using EtOAc/hexane (3:7) as eluent: low resolution MS (ES) m/e 364 (M-N2)\ <br><br> Intermediate 122 <br><br> 2-{2-iodo-phenylamino]-3-{4-(2-&lt;5-methyl-2'phenyl-oxazol-4-yl)-ethoxy]-phenyl&gt;-10 propionic acid methyl ester <br><br> The title compound (3.93 g) was prepared from Intermediate 121 (3.08 g, 7.87 mmol), 2-iodoaniline (2.07 g, 9.44 mmol) and Rh2OAc4 (100 mg) according to the method of Intermediate 3 followed by purification via silica gel chromatography with hexane/EtOAc (85:15): low resolution MS (ES*) m/e 583 (MH*). <br><br> 15 <br><br> Intermediate 123 <br><br> 2-[2-(4-formyl-benzoyl)-phenylamino]-3-{4-[2-(5-fnethyl-2-phenyUoxazol-4-yl)-ethoxy)-phenyl&gt;-propionic acid methyl ester <br><br> A suspension of K2C03 (356 mg. 2.58 mmol) in dioxane (13 mL) containing 20 Intermediate 122 (500 mg, 0.86 mmol), 4-formylphenyl boronic acid (193 mg, 1.29 mmol) and Pd(CI)2(PPh3)2 (18.0 mg. 26 mmol) was heated (100 *C) under 1 atm CO for 24 h. After cooling to RT. the mixture was partitioned between 50 mL each of water and EtOAc. The EtOAc solution was washed with 0.5 M NaOH (50 mL), water (50 mL) and brine (25 mL). This solution was dried over MgS04 and concentrated to 25 a brown oil which was flash chromatographed on silica gel (150 g) with hexane/EtOAc (85:15) to obtain unreacted starting iodide (0.32g, 64% yield) and the title compound (99.1 mg, 168 mmol, 20% yield) as a yellow oil: low resolution MS (ES) m/e 589 (MH*). <br><br> 30 Intermediate 124 <br><br> 2-[2-(3-formyl-b«nzoyl)-phenylamino]-3-{4-{2-(5-methyl-2-phenyl-ox«zol-4-yl)-Bthoxy]-phenyl)-propionic acid methyl ester <br><br> Following the procedure for Intermediate 123 using 3-formyl benzeneboronic acid, the title compound was isolated (25% yield) as a yellow oil: low resolution MS (ES*) 35 m/e 589 (MH*). <br><br> Printed from Mimosa <br><br> WO 97/31907 PCT/EP97/00916 <br><br> 71 <br><br> Intermediate 125 <br><br> 2(S)-(1-methoxycarbonyl-2-{4-{2-(S-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethylanrnio)-toenzoic acid methyl ester 5 A solution of Intermediate 120 (664 mg, 1.75 mmol) and methyl cyclohexanone-2-carboxylate (300 mg, 1.92 mmol) in toluene (50 mL) was refluxed for 16 h under N2 into a Dean-Stark trap (oil bath temp of 130°). The toluene was then removed by rotary evaporation and replaced with anisoie (50 mL). To this solution was added 10% palladium on carbon (250 mg) and the resulting suspension heated to 190" and 10 stirred for 6 h under N2. After cooling to room temperature the catalyst was removed by filtration through a pad of Celite (5 g) with an EtOAc wash (200 mL). The filtrate was concentrated to a brown oil which was flash chromatographed on silica gel (100 g) with hexane/EtOAc (4/1) to provide the title compound (590 mg, 66%) as a white solid: mp 102-103 °C; low resolution MS (ES*) m/e 515 (MH*). <br><br> 15 <br><br> Intermediate 126 <br><br> 2-(SH1*fn0thoxycarbonyl'2-{4-{2-(5-methyl-2-phenyl-oxazoM-yl)*0thoxy]-phenyl)'0thylamino)-b«nzoic add <br><br> A suspension of K2C03 (267 mg, 1.9 mmol) in dioxane (50 mL) and water (0.1 mL) 20 containing Intermediate 122 (375.2 mg, 0.64 mmol) and Pd(CI)2(PPh3)2 (22.6 mg, 0.032 mmol) in a 250 mL volume Parr bomb was stirred at 125° under CO (200 psi) for 16 h. After cooling to room temperature and venting the CO, the resulting mixture was diluted with EtOAc (250 mL) and washed with 2.0 M HCI and brine (50 mL each). The organic solution was dried over MgS04 and concentrated to a brown oil 25 which was flash chromatographed on silica gel (50 g) with EtOAc/hexane (1/1 with 0.1% HOAc) to afford the title compound (110 mg, 34%) as a white solid: mp 173-174 °C; low resolution MS (ES+) m/e 501 (MH*). <br><br> Intermediate 127 <br><br> 30 (2S)-2-(1-m«thoxycarbonyl-2-{4-hydroxy;&gt;henyl}-ethylamino)-benzoic acid methyl ester <br><br> A solution of 20.0 g (0.10 mol) of (L)-tyrosine methyl ester and 28.8 g (0.18 mol, 1.8 equiv.) of methyl cyclohexanone-2-carboxylate in 300 mL of toluene is heated to reflux for 2 h, with removal of H20 via a Dean-Stark trap. The resulting yellow 35 solution was cooled to RT and the toluene was removed in vacuo. The residue was <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 72 <br><br> PCT/EP97/00916 <br><br> dissolved in 250 mL of anisoie, and 5.0 g of 10% Pd/C was added. The resulting mixture was heated in 200 °C for 7 h, cooled to RT, an additional 5.0 g of 10% Pd/C was added and the mixture reheated to 200 °C for an additional 7 h. The reaction mixture was cooled to RT and filtered through a pad of Celite to remove the Pd. The 5 filtrate was concentrated in vacuo at 60 *C, and the residue purified by silica gei flash column chromatography using hexane / EtOAc 7/3 as eluent to afford a light yellow solid. This material was triturated with diethyl ether / hexane 1/1 and filtered to afford 15.75 g (47%) of the title compound as a white solid: low resolution MS (ES*) m/e 330 (MH*). <br><br> 10 <br><br> 2-{4-[2-(benzoxazol-2-yl-m0thyl-amino)-«thoxy}-benzyl}-3-(3-benzyloxy-phenyl)- <br><br> 3-hydroxy-2,3-dihydro-1H-indole-2-carboxyllc acid methyl aster <br><br> The title compound (1.45 g) was prepared from 2.09 g (5.49 mmol) Intermediate 9, 15 2.0 g (6.59 mmol) of (2-amino-phenyl)-(4-benzyloxy-pheny0-methanone (J. Org. Chem., 1991, 56 (11), 3750-3752) and 120 mg (0.27 mmol) ;f rhodium (II) acetate dimer according to the method of Intermediate 3 followed by purification via silica gel chromatography using EtOAc/hexane (gradient of 2:3 to 1:1) as eluent: low resolution MS (ES) m/e 678 (MNa*), 656 (MH*). <br><br> 20 <br><br> Intermediate 129 <br><br> 3-{4-[2-(bsnzoxazol-2-yl-msthyl-«mino)-«thoxy]-phenyl}-2-[2-&lt;3-b«nzyloxy-bsnzoyl)-phsnylsmino propionic acid methyl sstsr <br><br> To a stirred solution of 1.45 g (2.21 mmol) of Intermediate 128 in 22 mL of toluene 25 was added 1.1 mL (7.52 mmol) of 1,8-Diazabicyclo[5.4.0]undec-7-cne. The resulting solution was heated to reflux for 16 h. After cooling to RT, the solvent was removed in vacuo. The residue was purified by silica gel chromatography using EtOAc/hexane (gradient of 2:3 to 1:1) as eluent to give 1.02 g (70% yield) of the title compound: low resolution MS (ES) m/e 678 (M+Na*), 656 (MH*). <br><br> 30 <br><br> Intermediate 130 <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-«thoxy]-phenyl}-2-{2-(3-hydroxy-benzoyl)-phenylamino]-propionic acid methyl ester <br><br> A solution of 600 mg (0.91 mmol) of Intermediate 129 in 9 mL of EtOAc was 35 evacuated and flushed with argon. To the solution was added 300 mg (50 wt %) of <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 73 <br><br> Palladium on carbon (10%). The resulting slurry was evacuated and flushed with argon. After stirring under 1 atm of hydrogen for 16 h, the reaction was filtered through celite under a stream of nitrogen. The organics were collected and the solvent removed in vacuo to yield the title compound which was used directly without 5 further purification: low resolution MS (ES) m/e 588 (MNa*), 566 (MH*). <br><br> Intermediate 131 <br><br> 3-{4-[2-(5-methyl-2-|0henyl-oxa&lt;co!-4-yl)-ethoxy]-phenyl}-2-[2-(4-propylsulfamoyl-berczoyl)-phenylamino]-propionic acid methyl ester <br><br> 10 The title compound (70 mg) was prepared from 190 mg (0.77 mmol) 4-propylsulfamoyl-benzene boronic acid and 300 mg (0.52 mmol) of Intermediate 122 according to the method of Intermediate 126 followed by purification via silica gel chromatography using EtOAc/hexane (1:2) as eluent: low resolution MS (ES) m/e 704 (MNa*), 682 (MH" ). <br><br> 15 <br><br> Intermediate 132 <br><br> 2-[2-(3-amino-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-•thoxy]-phenyl)-propionic acid methyl eater <br><br> The title compound (640 mg) was prepared from 400 mg (2.58 mmol) 3-20 aminobenzene boronic acid and 1.0 g (1.72 mmol) of Intermediate 122 according to the method of Intermediate 126 followed by purification via silica gel chromatography using EtOAc/hexane (2:3) as eluent: low resolution MS (ES) m/e 598 (MNa*), 576 (MH*). <br><br> 25 Intermediate 133 <br><br> 2-[2-&lt;3-methanesulfonyliimino-benzoyl)-phanylamino]-3-{4-[2-&lt;5-mflthyl-2-phenyl-oxazol-4-yl)-ethoxy]-phcnyl}-propionic acid methyl ester <br><br> To a stirred solution of 150 mg (0.26 mmol) of Intermediate 132 in 3 mL of dichloromethane at 0°C was added 0.06 mL (0.78 mmol) of pyridine and 0.02 mL 30 (0.29 mmol) of methanesulfonyl chloride. After warming to RT over 1.25 h, the reaction was washed with Sat. NaHC03 and water, the layers separated, organics dried (Na2S04), and the solvent removed in vacuo. The residue was purified by silica gel chromatography with EtOAc/hexane (1:1) as eluent to give 60 mg (35% yield) of the title compound: low resolution MS (ES) m/e 654 (MH*). <br><br> . 35 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 74 <br><br> Intermediate 134 <br><br> 2-{2-(3-methoxycarbonylamino-benzoyl)-phenylamfno]-3-{4-{2-{5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid mothyl ester <br><br> To a stirred solution of 180 mg (0.31 mmol) of Intermediate 132 in 3 mL of 5 dichloromethane was added 65 mL (0.47 mmol) of triethylamine. The solution was cooled to 0°C and 0.27 mL (0.34 mmo!) of methylchlorofcrmate added. After warming to RT overnight, the solvent was removed in vacuo and the residue purified by silica gel chromatography using EtOAc/hexane (2:3) as eluent to give 50 mg (25% yield) of the title compound: low resolution MS (ES) m/e 634 (MH*). <br><br> 10 <br><br> tntonrrcdfrfr 135 <br><br> 2-(2-(3-benzyloxy-benzoyl)-phenylamino]-3-{4-[2-(5-fnethyl-2-phsnyl-oxazol-4-yl)-ethoxy]-phenyi}-propionic acid methyl ester <br><br> The title compound (580 mg) was prepared from 480 mg (2.06 mmol) 3-benzyloxy 15 benzene boronic acid and 0.8 g (1.37 mmol) of Intermediate 122 according to the method of Intermediate 126 followed by purification via silica gel chromatography using EtOAc/hexane (gradient of 3:17 to 1.4) as eluent. low resolution MS (FAB) m/e 667 (MH*). <br><br> 20 Intermediate 136 <br><br> 2-{2-(3-hydroxy-benzoyl)-phenylamino]-3-{4-t2-{5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester <br><br> A solution of 100 mg (0.15 mmol) of Intermediate 135 in 1.5 mL of EtOAc was evacuated and flushed with argon. To the solution was added 110 mg (100 wt %) o; 25 Palladium on carbon (10%). The resulting slurry was evacuated and flushed with argon. After stirring under 1 atm of hydrogen for 16h, the reaction was filtered through celite under a stream of nitrogen. The organics were collected and the solvent removed in vacuo. The residue was purified by silica gel chromatography using EtOAc/hexane (3:7) as eluent to give 56 mg (37% yield) of the title compound: 30 low resolution MS (FAB) m/e 577 (MH*). <br><br> Intennftfipft 1?7 <br><br> 2-[2-(3-carbanoylm0thoxy-benzoyl)-ph«nylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol&lt;4&gt;yl)-ethoxy]-phenyl}-propionic acid methyl ester <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 75 <br><br> To a stirred solution of 100 mg (0.17 mmol) of Intermediate 136 in 2 mL of anhydrous THF at 0 °C was added 8 mg (0.19 mmol) of a 60% suspension of NaH. After stirring for 5 min, 24 mg (0.17 mmol) of 2-bromoacetamide was added to the slurry. The solution was warmed to RT, diluted with water, and extracted with 5 EtOAc. The layers were separated, the organics dried (Na2S04), and the solvent removed in vacuo to give a yellow solid. The solid was purified by trituration with hexane to give 73 mg (66% yield) of the title compound: low resolution MS (ES) /rvfe 656.2 (MNa*), 634 (MH*). <br><br> 10 Intermediate 138 <br><br> 3-azido-4-oxo-pentanoic acid methyl ester <br><br> To a solution of 2.23 g (10.67 mmol) of 3-bromo-4-oxo-pentanoic acid methyl ester in 11 mL of DMF at 0°C was added 690 mg (10.67 mmol) of sodium azide. After warming to RT over 2.5 h, the reaction was diluted with water and extracted with 15 diethyl ether/hexane (1.1). The layers were separated, the organics dried (Na2S04), and the solvent removed in vacuo. The residue was purified by silica gel chromatography using diethyl ether/hexane (gradient of 1:4 to 2:3) to give 1.07 g (58% yield) of the title compound: low resolution MS (FAB) m/e 172 (MH*). <br><br> 20 Intermediate 139 <br><br> 3-amino-4-oxo-pentanoic acid methyi ester <br><br> A solution of 1.0 g (5.8 mmol) of Intermediate 138 in 25 mL of MeOH was evacuated and flushed with argon. To the solution was added 290 mg (30 wt %) of Palladium on carbon (10%). The resulting slurry was evacuated and flushed with argon. After 25 stirring under 1 atm of hydrogen for 4h, the reaction was filtered through celite under a stream of nitrogen. The organics were collected and the solvent removed in vacuo to give 940 mg (90% yield) of the title compound which was used without further purification: low resolution MS (ES) m/e 146 (MH*). <br><br> 30 Intermediate 140 <br><br> 4-oxo-3-[(pyridin»-4-carbonyl)-amino]-p*ntanoic acid methyl ester <br><br> To a stirred solution of 940 mg (5.18 mmol) Intermediate 139 in 52 mL of dichloromethane at 0°C was added 2.9 mL (20.72 mmol) of triethyl?mine. After stirring for 5 min, 1.0 g (5.69 mmol) of isonicotinoyl chloride hydrochloride was 35 added and the reaction allowed to warm to RT overnight. The stirred solution was <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 76 <br><br> diluted with water, the layers separated, organics dried (MgS04), and the solvent removed in vacuo. The residue was purified by silica gel chromatography using MeOH/ EtOAc (gradient of 0:1 to 1:19) to give 360 mg (28% yield) of the title compound: low resolution MS (ES) m/e 251 (MH*). <br><br> 5 <br><br> Intermediate 141 <br><br> (5-m«thyl-2-pyridin-4-yl-oxazol-4-yl)-acetic acid methyl ester <br><br> To a stirred solution of 250 mg (1.0 mmol) of Intermediate 140 in 7 mL of anhydrous toluene was added 0.28 mL (3.0 mmol) of POCI3 (fresh ampule) and the reaction 10 heated to reflux for 16 h. After cooling io RT, the reaction was diluted with EtOAc and the organics washed with Sat. NaHC03, dried (MgS04), and the solvent removed in vacuo. The residue was purified by silica gel chromatography using MeOH/EtOAc (1:19 with 0.1% NH4OH) as eluent to give 180 mg (78% yield) of the title compound: low resolution MS (ES) m/e 233 (MH*). <br><br> 15 <br><br> Intermediate 142 <br><br> 2-{5-methyl-2-pyridin-4-yl-oxizol-4-yl)-ethanol <br><br> The title compound (200 mg) was prepared from 285 mg (1.23 mmol) of Intermediate 141 according to the method of Intermediate 43 followed by purification 20 via silica gel column chromatography using MeOH/EtOAc (1:19) as eluent: low resolution MS (ES) m/e 205 (MH*). <br><br> Inftrnwltaft 143 <br><br> 2(SH2-benzoyl-phenyl«mino)-3-{4-(2-&lt;5-methyl-2-pyridin-4-yl-oxazol-4-yl)-25 ethoxy]-phenyl)-propionic acid methyl ester <br><br> The title compound (210 mg) was prepared from 0.15 g (0.73 mmol) of Intermediate 142 and 0.27 g (0.73 mmol) of Intermediate 23 according to the method of Intermediate 44 followed by purification via silica gel chromatography using EtOAc/hexane (gradient of 1:1 to 9:1): low resolution MS (ES) m/e 562 (MH*). <br><br> 30 <br><br> Intermediate 144 <br><br> 4-tert-butoxycarbonyl-piperazine-1-cartx&gt;thioic acid amide <br><br> The title compound (1.5 g) was prepared from 3.01 g (16.91 mmol) of thiocarbonyldiimidazole and 3.0 g (16.12 mmol) of 1 -ferf-butoxycarbonyl-piperazine <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 77 <br><br> PCT/EP97/00916 <br><br> according to the method of intermediate 53 followed by purification via trituration with diethyl ether: low resolution MS (ES) m/e 246 (MH*). <br><br> intermediate 145 <br><br> 5 (5-methy l-2-{4-tert-butoxycarbonyl-piperazfn-1 -yl)-thiazol-4-yl]-acetic acid methyl ester <br><br> The title compound (1.18 g) was prepared from 1.2 g (4.89 mmol) of Intermediate <br><br> 144 and 1.02 g (4.89 mmol) of methyW-bromo-3-oxo-pentanoate according to the method of Intermediate 60 followed by purification via silica gel chromatography <br><br> 10 using MeOH/dichloromethane (1:19) as eluent: low resolution MS (ES) m/e 356 (MH*). <br><br> Intermediate 145 <br><br> 2-{5-methyl-2-(4-tert-butoxycarbonyl-piperazin-1-yl)-thiazol-4-yl]-ethanol <br><br> 15 The title compound (820 mg) was prepared from 1.0 g (2.81 mmol) of Intermediate <br><br> 145 according to the method of Intermediate 43 followed by purification via silica gel chromatography using MeOH/dichloromethane (1:19) as eluent: low resolution MS (ES) m/e 328 (MH*). <br><br> 20 Intermediate 147 <br><br> 2(SH2-benzoyl-phsny!amino)-3-(4-{2-{5-methyl-2-(4-tert-butoxycarbonyl-piperazin-1-yl)-thiazol-4-yl]-«thoxy&gt;*phenyl)-propionlc acid methyl ester <br><br> The title compound (490 mg) was prepared from 300 mg (0.92 mmol) of Intermediate 146 and 330 mg (0.87 mmol) of Intermediate 23 according to the 25 method of Intermediate 45 followed by purification via silica gel chromatography using MeOH/dichloromethane (1:49) as eluent: low resolution MS (ES) m/e 707 (MNa*), 685 (MH*). <br><br> 'nftrmrtlntf 148 <br><br> 30 2(S)-(2-befUoyl-phenylamino)-?-{4-{2-&lt;5-methyl-2-piperazin-1-yl-thiazol-4-yl)-ethoxy]*phenyl)-propionic acid methyl ester <br><br> To a stirred solution of 650 mg (0.95 mmol) of Intermediate 147 in 10 mL of dichloromethane was added 1 mL of trifluoroacetic acid. After stirring for 1.5 h, the reaction was washed with water and Sat. NaHC03. The layers were separated, the 35 organics dried (MgS04), and the solvent removed in vacuo. The residue was <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 78 <br><br> purified by silica gel chromatography using MeOH/EtOAc (1:4) as eluent to give 176 mg (32% yield) of the title compound: low resolution MS (ES) m/e 607 (MNa*), 585 (MH+). <br><br> 5 intermediate 148 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-mothyl-2-(4-methyisulfonyl-piperazin-1-yl)-thiazol-4-y!]-ethoxy}-phenyl)-propionic acid methyl ester <br><br> To a stirred solution of 170 mg (0.29 mmol) of Intermediate 148 in 3 mL of dichloromethane at 0°C was added 0.07 mL (0.87 mmol) of pyridine and 0.025 mL 10 (0.32 mmol) of methanesulfonyl chloride. After warming to RT, the reaction was washed with Sat. NaHC03 and water. The layers were separated, the organics dried (MgS04), and the solvent removed in vacuo. The residue was purified by silica gel chromatography using EtOAc/hexane (2:1) as eluent to give 140 mg (74% yield) of the title compound: low resolution MS (ES) m/e 663 (MH*). <br><br> 15 <br><br> Intermediate 150 <br><br> 2(S)-(2-{4-[2-(S-methyl-2-phenyl-thlazol~4~yl)-ethoxy]-phenyl}-1-methoxycarbonyl-ethylamino)-benzoic acid methyl ester <br><br> A suspension of 350 mg (1.37 mmol. 1.10 equiv) of triphenylphosphine, 395 mg 20 (1.20 mmol) of Intermediate 127, and 290 mg (1.32 mmol) of Intermediate 106 in 10 mL of dry toluene was heated to 80 *C for 15 min to effect dissolution of Intermediate 127 to provide a clear colorless solution. To this solution was added 250 mg (1.26 mmol, 1.05 equiv) of diisopropyl azodicarboxylate dropwise over 5 min. The reaction was then allowed to cool to RT and stirred 16 h. The toluene was 25 removed in vacuo, and then the residue was stirred vigorously for 1 h in 10 mL of 1:1 diethyl ether / 1 N LiOH biphasic solution to effect selective removal of residual Intermediate 127. The layers were separated and the organic layer washed with H20, dried (MgS04), and solvent removed in vacuo. The material was purified by silica gel flash column chromatography using hexane / EtOAc 5 / 1 as eluent to 30 afford 400 mg of the title compound as a white solid: low resolution MS (FAB)m /e 531 (MH*). <br><br> Intermediate 151 <br><br> 2(SM2-{4-{2-(4-chloro-phenyl«ulfanyl)-ethoxy]-phenyl)-1-m*thoxycarbonyl-35 ethylamino)-benzoic acid methyl ester <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 79 <br><br> PCT/EP97/00916 <br><br> The title compound (118 mg) was prepared from 100 mg (0.30 mmol) of Intermediate 127 and 69 mg (0.36 mmol) of 2-(4-chlorophenylthio)-ethanol according to the method of Intermediate 150 followed by purification via silica gel flash column chromatography using hexane / EtOAc 5 / 1 as eluent: low resolution 5 MS (FAB)m/e 500 (M ). <br><br> Intermediate 152 <br><br> 2(SH2-{4-[2-(5-nitro-2-pyridyloxy)-ethoxy]-phenyl}-1-methoxycarbonyl-ethylamino)-benzoic acid methyl ester <br><br> 10 The title compound (109 mg) was prepared from 139 mg (0.754 mmol) of 2-(5-nitro-2-pyridyloxy)ethanol and 248 mg (0.754 mmol) of Intermediate 127 according to the method of Intermediate 150 followed by purification via flash chromatography (2:1Hex:EtOAc): low resolution MS m/e 496 (MH+). <br><br> 15 Intermediate 153 <br><br> 2(S)-(2-(4-t2-(5-chloro-2-pyridyl9ulfanyl)-ethoxy]-phenyl)-1-methoxycarbonyl-ethylamlno)-benzoic acid methyl ester <br><br> The title compound (155 mg) was prepared from 156 mg (0.824 mmol) of 2-(5-chloropyrid-2-ylthio)ethanol and 271 mg (0.824 mmol) of Intermediate 127 according 20 to the method of Intermediate 150 followed by purification via flash chromatography (4:1 Hex:EtOAc): *H NMR (CDCI3. 400 MHz) &amp; 8.39 (d. 1H, 2.3). 8.19 (d, 1H). 7.89 (dd. 1H, 1.5, 8.0). 7.78 (d. 1H, J = 2.5). 7.45 (dd. 1H. J = 2.4. 8.5), 7.14 (d. 4H, J - 8.5), 6.86 (d. 2H. 8.5), 6.62 (t, 1H, 7.6). 6.54 (d. 1H. J = 8.4), 4.33 (q. 1H, J = 6.7), 4.19 (t, 2H. J = 6.7). 3.85 (s. 3H), 3.67 (s. 3H). 3.52 (t. 2H. J = 6.7), 3.12 (ddd. 2H. J 25 = 5.4, 7.1. 7.1). <br><br> Intermediate 164 <br><br> 2(SH2-(4-{2-(N-«thyl-2-methyl-toluidino)-«thoxy]-phenyl}-1&lt;methoxycarbonyl-ethylamino)-b«nzolc acid methyl ester <br><br> 30 The title compound (90 mg) was prepared from 123 mg (0.687 mmol) of 2-(N-ethyl-m-toluidino)ethanol and 226 mg (0.6B7 mmol) of Intermediate 127 according to the method of Intermediate 150 followed by purification via by flash chromatography (4:1 Hex:EtOAc): low resolution MS m/e 491 (MH+). <br><br> 35 Intermediate "tS5 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 80 <br><br> 2(S)-{2-{4-[2-(4-dimethylamino-ph*nyl)-ethoxy]-phenyl}-1-methoxycarbonyl-ethylamino)-benzoic acid methyl ester <br><br> The title compound (290 mg) was prepared from 110 mg (0.64 mmol) of 4-(dimethylamino) phenethyl alcohol and 200 mg (0.61 mmol) of Intermediate 127 5 according to the method of Intermediate 150 followed by purification via silica gel chromatography using triethylamine/EtOAc/hexane (1:4:15) as eluent: low resolution MS (ES) m/e 499 (MNa*). <br><br> Intermediate 156 <br><br> 10 2(S)-[1 -methoxycarbonyl-2-(4-{2-[5-methyl-2-(4-methyl-pip«razin-1 -y l)-thiazol-4-yl]-ethoxy}-phenyl)-ethylamino]-benzoic acid methyl ester <br><br> The title compound (360 mg) was prepared from 187 mg (0.77 mmol) of Intermediate 71 and 240 mg (0.74 mmol) of Intermediate 127 according to the method of Intermediate 150 followed by purification via silica gel chromatography 15 using MeOH/EtOAc (1:9) as eluent: low resolution MS (ES) m/e 553 (MH*). <br><br> Intermediate 157 <br><br> 2(S)-(2-{4*{2-(4-chloro-phenyl)-0thoxy]-phenyl}-1-methoxycarbonyl-ethylamlno)-benzoic acid methyl ester <br><br> 20 The title compound (230 mg) was prepared from 100 mg (0.64 mmol) of 4-chloro phenethyl alcohol and 200 mg (0.61 mmol) of Intermediate 127 according to the method of Intermediate 150 followed by purification via silica gel chromatography using EtOAc/hexane (1:3 with 1% TEA) as eluent: low resolution MS (ES) m/e 490 (MNa*), 468 (MH*) <br><br> 25 <br><br> inftfiraMito <br><br> 2-&lt;4-irifluoromethoxy-phenyl)-ethanol <br><br> To a stirred solution of 1.0 g (4.54 mmol) of 4-(trifluoromethoxy)-phenylacetic acid in 15 mL of anhydrous THF at 0°C was added dropwise 9 mL (9.08 mmol) of 1 M 30 BHj THF und the reaction allowed to warm to RT over 16 h. The mixture was cooled back down to 0°C and the reaction quenched with 15 mL of water/acetic acid/THF (1:1:3). After warming to RT, the solvent was removed in vacuo, the residue diluted with water, and the solution extracted with EtOAc. The layers were separated, the organics washed with NaHCOj, the layers separated, the organics dried (MgS04), 35 and the solvent removed in vacuo. The residue was purified by silica gel <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 81 <br><br> chromatography using EtOAc/hexane (1:1) as eluent to give 540 mg (57% yield) of the title compound: TLC (EtOAc/hexane (1:1)): Rf = 0.43. <br><br> Intermediate 159 <br><br> 5 2(S)-(1-methcxycarbonyl-2-{4-{2-(4-ti1fluoromathoxy-phenyl)-ethoxy]-phenyl}-ethy!amlno)-benzoic acid methyl ester <br><br> The title compound (280 ir.g) was prepared from 130 mg (0.64 mmol) of Intermediate 158 and 200 mg (0.61 mmol) of Intermediate 127 according to the method of Intermediate 150 followed by purification via silica gel chromatography 10 using EtOAc/hexane (1:3) as eluent: low resolution MS (ES) m/e 540 (MNa*). <br><br> Intermediate 160 <br><br> 2-{4-[2-(Benzoxazol-2-yl-methylamino)-ethoxy]-benzyl}-3-hydroxy-?- henyl-2,3-dihydro-1H-thieno[3,4-b]pyrrole-2 carboxylic acid methyl ester <br><br> 15 The title compound (100 mg) was prepared from 196 mg (0.52 mmol) of Intermediate 9 and 160 mg (0.79 mmol) of 2-amino-3-benzoylthiophene (Hromatka, O. et. al., Monatsh. Chem. 1973, 104(6). 1513-19) according to the method of Intermediate 3 followed by purification via silica gel chromatography eluting with 20-40% EtOAc in hexanes: low resolution MS (CI) m/e 556 (MH*) <br><br> 20 <br><br> Intermediate 161 <br><br> 3-&lt;4-Hydroxypb»nyl)-2-{2-(4-biph»nylcart&gt;onyl)-ph®nylffimino)-propionic acid methyl ester <br><br> The title compound (830 mg) was prepared from 1.83 g (5.7 mmol) O-benzyl-L-25 tyrosine methyl ester and 1.59 g (5 7 mmol) of 2-(4-phenylbenzoyl)cyclohexanone (Child, R.G. et.al. J. Pharm Sci 1977, 66(4), 466-76) according to the method of Intermediate 23 followed by purification via silica gel chromatography eluting with 1/9 EtOAc/hexanes: Low resolution MS (CI) m/e 452 (MH ). <br><br> 30 Intermediate 162 <br><br> 3-{4-[2-{B«nzoxazol-2-yl-methylamino)-ethoxy]-ph*nyl}-2-{2-(4-biphenylcarbonyl)-phenylamino)-propionlc acid methyl ester <br><br> To a DMF solution (5 mL) of Intermediate 161 (0.78 g, 1.73 mmol) was added 57 mg of 80% NaH followed by 0.47 g (1.73 mmol) of Intermediate 6 in 5 mL DMF. The 35 mixture was stirred for 18 h at 80 C, quenched with water (5 mL), concentrated to <br><br> Printed from Mimcsa <br><br> WO 97/31907 <br><br> FCT/EP97/00916 <br><br> 82 <br><br> dryness, and extracted from 30 mL water with EtOAc(3 X 30 mL). The organics were dried (MgS04), concentrated, and purified by silica gei chromatography eluting with 1/1 EtOAc/hexanes to give 0.90 g of the title compound: low resolution MS (CI) m/e 626 (MH+) <br><br> 5 <br><br> Intermediate 163 <br><br> 3-(4-Hydroxyphenyl)-2-(2-{4-n-i«thoxybenzoyl)-ph«ny!amino)-propionic acid methyl ester <br><br> The title compound (2.31 g) was prepared from 4.64 (20 mmol) of 2-(4-10 methoxybenzoyl)-cyciohexanone (Howard, A.S. et. al. Tetrahedron Lett. 1979, (15), 1339-40) and 6 43 g (20 mmol) of O-benzyl-L-tyrosine methyl ester hydrochloride as a yellow solid as described for Intermediate 161: low resolution MS (CI) m/e 406 (MH*). <br><br> 15 |nftrn»MHiift 1$4 <br><br> 3-{4-{2-{Benzoxazol-2-yl-methyiamino)-«thaxy]-phenyl}-2-{2-{4-methoxybenzoyl)-phenylaminoH&gt;ropionic acid methyl ester <br><br> The title compound (J.34 g) was prepared from Intermediate 163 (0.5 g, 1.23 mmol) and Intermediate 6 (0.33 g, 1.23 mmol) as described above for Intermediate 162: 20 low resolution MS (CI) m/e 581 (MH*). <br><br> Intermediate 16S <br><br> 3-{4-[2-(Benzoxa2ol-2-yl-methylamino)-«thoxy]-phenyl)-2-(2-(4-n)ethylbenzoyl)-phenylsmino)-propionic acid methyl ester <br><br> 25 The title compound (810 mg) was prepared from 0.6 g (1.58 mmol) Intermediate 9 and 1.0 g (4.73 mmol) of 2-pmino-4'-methylbenzophenone (Prye, S.V. et. al. J. Org. Cham. 1991, 50(11), 3750-52) according to the method of Intermediate 3 followed by purification via silica gel chromatography eluting with 30-50% EtOAc in hexanes: low resolution MS (ESP*) m/e 586 (M + Na*). <br><br> 30 <br><br> Intermediate 166 <br><br> 3-{4-{2-(Benzoxazol-2-yl-methylamino)-ethoxy]-phenyl)-2-(2-{2-methylbenzoyl)-phenylamino)-propk&gt;nic acid methyl ester. <br><br> The title compound (800 mg) was prepared from 628 mg (1.65 mmol) of 35 Intermediate 9 and 523 mg (2.48 mmol) of 2-amino-2'-methylbenzophenone (Frye, <br><br> Printed from Mimosa <br><br> 83 <br><br> S.V. e:. al. J. Org. Chem. 1991, 56(11), 3750-52) according to the method of Intermediate 3 followed by purification via s'lica gel chromatography, eluting with 20-40% EtOAc in hexanes: low resolution MS (CI) m/e 564 (MH*). <br><br> EXAMPLES <br><br> The compounds of Examples 43, 44, 47, 49, 69, 76, 77, 85, 90, 92, 94, 97,109,121 and 128 fall outside the scope of formula (I) and are therefore not compounds according to the present invention. <br><br> Example 1 <br><br> 3H4-Benzyloxy-phenyl)-2(S)-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid dicyclohexylamine salt <br><br> A stirred mixture of 5.42 g (20 mmol) o-benzyl-L-tyrosine, 4.4 mL (22 mmol) dicyclohexylamine and 3.24 g (20 mmol) 1-benzoylacetone in 100 mL MeOH was refluxed for 24 h. 500 mL abs. ethanol was then added slowly to the solution and the MeOH was distilled out from the reaction flask with the same rate. The solution was then cooled to 0°C, stirred for 30 min, then filtered. The white solid was washed with 15 mL cold (- 20 °C) abs. ethanol three times then dried to yieid 7.60 g of the title compound: low resolution MS (FAB+) m/e 597 (MH+), 182 (DCAH+); Anal. (C38H4flN204) Calcd. C, 76.47; H, 8.10; N, 4.69 Found C, 76.44; H, 8.16; N 4.63. <br><br> Example 2 <br><br> 3-{4-Benzyloxy-phenyl)-2(SM1-methyl-3-oxo-3-phenyl&gt;propenylamino)-propionic acid methyl ester <br><br> To a stirred suspension of 2.98 g (5 mmol) of Example 1 and 1.50 g (10.8 mmol) anhydrous potassium carbonate in 30 mL anhydrous dimethylformamide 0 37 mL (6 mmol) methyl iodide was added in one portion. The mixture was stirred for 1 h, then an additional amount of 0.5 mL (8 mmol) methyl iodide was added. The suspension was stirred for an additional 20 min, then it was diluted with 100 mL ether. 100 mL brine was added, and the phases were separated. The organic phase was extracted with 200 mL brine six times, then the organic phase was dried with anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure The residue was purified by flash chromatography (Si02, eluent: Hexane/EtOAc(5:1) then hexane/EtOAc (1:1)) to yield 1.4 g of the of the title compound: low resolution MS (ESP+) m/e 430 (MH+); Anal. (C27H27N04) Calcd. C, 75.50; H, 6.33; N, 3.26 Found C. 75.41; H, 6.35; N 3.28 <br><br> INTELLECTUAL PROPER"™ OFFICE OF N.Z. <br><br> 2 8 APR 2000 <br><br> Example 3 <br><br> 2(SH2-Benzoyl-cyclohex-1-enylamino)-3-(4-benzyloxy-pher&gt;yl)-propionic acid dicyclohexylamine salt <br><br> A stirred mixture of 1.35 g (5 mmol) o-benzyl-L-tyrosine, 1.0 mL (5 mmol) dicyclohexylamine and 1.01 g (5 mmol) 2-benzoylcyclohexanone (Denny, William A.; Cain, Bruce F.;J. Med. Chem. (1978), 21(5), 430-7.) in 25 mL MeOH was refluxed for 24 h. The solution was then cooled to 20 DC, and the solvent was evaporated under reduced pressure. Purification of the residue by flash chromatography using Hexane/EtOAc (1:1) then EtOAc (neat), finally CHCIj/MeOH (10:1) as eluents resulted in 1.4 g of the of the title compound. 1H NMR (DMSO-d6, 400 MHz) 6 12.00 (d, 1H, J-8.4) 7.3 (m, 10H), 7.13 (d, 2H, 8.5), 6.85 (d, 2H, J= 8.5), 5.01 (s. 2H), 4.02 (m, 1H), 3.05 (m, 1H), 2.89 (m, 2H). 2.73 (dd, 1H, 13.7), 2.25 (m, <br><br> 1H), 2.03 (m, 3H)1.93 (m, 3H), 1.66 (m, 3H), 1.53 (d, 2H, J=12.3), 1.30 (m, 2H), 1.20 (m, 12H), 1.03 m (2H); low resolution MS (ESP+) m/e 456 (MH+). <br><br> Example 4 <br><br> 15 2-(2-benzoylphenylamino)-3-(4-benzyloxyphenyl) propanoic acid <br><br> To a solution of 185 mg (0.62 mmol) of Intermediate 2 in 8 mL (1:1; dioxane:water) was added 500 mg (11.9 mmol) lithium hydroxide monohydrate. The resulting suspension was stirred at 50'C for 1 h and then cooled to RT. A 1M phosphoric acid solution was added until pH was 5.5 was reached where upon the resulting suspension was extracted with EtOAc (2 x 25 mL). The combined organic extracts 20 were dried (MgS04), filtered, and concentrated and chromatographed on silica gel ^ using CH2CI2/MeOH (9:1) to yield 133 mg of the title compound. 1H NMR (CDCI3) 5 8.87 (bs. 1H) 7.60 -7.58 (d, 2H, J = 6) 7.94-7.32 m (10H). 7.23-7.21 (d. 2H, J - 3.9), 6.90-6.88 (m, 2H) 6.67-6.56 (m, 2H), 4.98 (s. 2H), 4.39 (m, 1H), 3.30-3.10 (m, 2H); low resolution MS (FAB+) m/e (MH+) 452.1. <br><br> 25 Example 5 <br><br> 3-{4-Benzyloxy-phenyl)-2-(2-benzy!oxy-phenylamino)-propionic acid methyl ester <br><br> 3 mg (0.0067 mmol) rhodium(ll) acetate dimer was added to stirred solution of 150 mg (0 50 mmol) of Intermediate 1 (Kawamatsu, Y. at al Arzneim.-Forsch. 1980, 30(4), 585-9) and 113 mg (0.50 mmol) 2-Amino-benzoic acid benzyl ester in 5 mL toluene at 80 °C. The mixture was stirred at 80 "C for 5 min, then cooled to room temperature. The solvent was removed under i-pHmppH prf&gt;«t«snrp anH thp ryirhi* <br><br> INTELLECTUAL PROPERTY OFFICE OF N.Z. <br><br> 2 8 APR 2000 <br><br> WO 97/3J907 <br><br> PCT/EP97/00916 <br><br> 85 <br><br> was purified by flash chromatography using hexane/EtOAc (5:1) as eluent to yield 130 mg of the title compound. 1H NMR (CDCI3, 400 MHz) 8 8.19 (d, 1H, &gt;7.3), 7.95 (dd, 1H, &gt; 1.4. 7.9), 7.35 (m, 11H), 7.12 (d, 2H, &gt; 8.5), 6.87 (d, 2H. &gt; 8.5), 6.60 (t, 1H, &gt;7.5), 6 53 (d, 1H, &gt;8.6), 5.30 (s, 2H), 5.01 (s, 2H), 4.32 (q, 1H, &gt;6.4), 3.65 5 (s, 3H), 3.14 (dd. 1H, &gt;6.0, 13.6), 3.08 (dd, 1H, &gt;7.2, 13.7); low resolution MS (ESP+) m/e 496 (MH+). <br><br> Example 6 <br><br> 3-{4-B*nzyloxy-phenyl)-2-(phenylcarbamoyl-phenylamino)-propionic acid 10 methyl estar <br><br> The title compound (54 mg) was prepared from 150 mg (0.50 mmol) of Intermediate 1 (Kawamatsu, Y. at al. Arzneim.-Forsch. 198C, 30(4), 585-9) and 110 mg (0.51 mmol) 2-amino-benzanilide according to the method of Example 5: 1H NMR (CDCI3, 400 MHz) 6 7.83 (s, 1H), 7.66 (d, 1H, &gt;7.9), 7.54 (d. 2H, &gt;8.0), 7.47 (d. 1H, &gt;7.9), 15 7.35 (m, 8H), 7.13 (m, 3H), 6.85 (d. 2H, &gt;8.6), 6.68 (t, 1H. &gt;7.5), 6.61 (d, 1H, &gt;8.4), 4.96 (s, 2H), 4.30 (q, 1H, &gt;7.2), 3.64 (s. 3H). 3.10 (m, 2H); low resolution MS (ESP+) m/e 481 (MH+). <br><br> Example 7 <br><br> 20 3-(4-Benzyloxy-phanyl)-2-[2-{piperidine-1-carbonyl)-phenylamino]-propionic acid methyl aster <br><br> The title compound (90 mg) was prepared from 150 mi (0.50 mmol) Intermediate 1 (Kawamatsu, Y. atal. Arzneim.-Forsch. 1980, 30(4), 585-9) and 103 mg (0.50 mmol) 2-amino-phenyl)-piperidin-1-yl-methanone (Ahem, T. P., et al. Can. J. Chem. 1976, 25 54(2), 290-6.) according to the method of Example 5 followed by purification by silica gel flash chromatography using hexane/EtOAc (1:1) as eluent: 1H NMR (CDCI3, 400 MHz) 5 7 40 (m. 5H). 7.21 (t, 1H, &gt;8.2), 7.15 (m. 3H), 6.93 (d. 2H, &gt;8.7), 6.73 (t, 1H, &gt;7.4), 6.59 (d, 1H, &gt;8.2), 5.21 (d(broad), 1H, &gt;8.3), 5.06 (s, 2H), 4.30 (dd, 1H, &gt;7.9, 8.3), 3.69 (s, 3H). 3.45 (m, 4H), 3.10 (m, 2H), 1.55 (m, 6H); low resolution 30 MS (ESP+) m/e 473 (MH+). <br><br> Example 8 <br><br> 2-{3-Benzoyl-thiophen-2-yl-amino)-3-(4-benzyloxy-phenyl)-propionic acid <br><br> A solution of 100 mg (1.78 mmol) potassium hydroxide in 1 mL water was added to 35 a stirred solution of 120 mg (0.25 mmol) of Intermediate 3 in 10 mL MeOH. The <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 86 <br><br> mixture was stirred for 2 h at 20 aC then adjusted to pH=2 with 5% aqueous hydrochloric acid. 50 mL water was added to the mixture, the it was extracted with 20 mL methylene chloride three times. The organic phases were combined, dried with anhydrous magnesium sulfate, then concentrated under reduced pressure. The 5 residue was purified by silica gel flash chromatography using EtOAc(neat) then EtOAc/EtOH (1:1) solvent mixtures as eluents to provide 27 mg of the title compound. 1H NMR (DMSO-d6, 400 MHz) 6 9.68 (d, 1H, &gt;6.9), 7.45 (m, 10H), 7.14 (d, 2H, &gt;8.0), 6.86 (d, 2H. &gt;8.0), 6.80 (d, 1H. &gt;5.6), 6.27 (d, 1H, &gt;5.5), 5.03 (s. 2H), 3.80 (m, 1H), 3.23 (d, br, 1H, &gt;9.0), 3.06 (d, 1H, &gt; 9.5); low resolution MS 10 (ESP+) m/e 458 (MH+). <br><br> Example 9 <br><br> 2-(2-Benzoyl-thiophen-3-yl-amino)-3-(4-benzy!oxy-phenyl)-propionic acid <br><br> A solution of 300 mg (5.35 mmol) potassium hydroxide in 2 mL water was added to 15 a stirred solution of 280 mg (0.59 mmol) of Intermediate 4 in 10 mL MeOH. The mixture was stirred for 2 h at 20 °C then 50 mL water, 50 mL brine and 3 mL acetic acid was added The resulting emulsion was extracted with 20 mL methylene chloride three times. The organic phases were combined, dried with anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was 20 purified by silica gel flash chromatography using CH2CI2(neat), EtOAc/EtOH(9:1) and finally EtOH(neat) as eluents to provide 90 mg tile compound. 1H NMR (DMSO-d6. 400 MHz) 6 8.95 (d. 1H, &gt;7.7), 7.62 (m, 3H), 7.45 (m, 3H), 7.30 (m, 5H), 7.09 (d, 2H, &gt;8.4), 6.80 (d, 2H, &gt;8.2), 6.60 (d, 1H, &gt;5.5), 4.96 (s, 2H), 4.05 (m, 1H), 3.13 (d, br, 1H, &gt;11.8), 2.90 (dd, 1H, &gt;1.6, 3.4); low resolution MS (ESP+) m/e 458 25 (MH+). <br><br> Example 10 <br><br> 3-(4-Benzy;oxy-phenyl)-2(S)-{(4-oxo-4H-chromene-3-carbonyl)-amino]-propionic acid methyl ester. <br><br> 30 To a stirring solution of 360 mg (2 mmol) of chromone-3-carboxylic acid in 25 mL of CH2CI2 at 0°C were added several drops of DMF followed by 1 mL of 2M solution of oxalyl chloride in CH2CI2. The resulting solution was stirred 3 h at rt and 643 mg (2 mmol) of O-benzyl-L-tyrosine methyl ester hydrochloride and 0.2g (2.0 mmol) of triethylamine in 15 mL of CH2CI2 were added and stirring continued overnight. 35 Solvent was removed under reduced pressure. Product was purified by LCC on <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EF97/00916 <br><br> 87 <br><br> Si02 (Hexane . EtOAc 13 :7) providing 83 mg of title compound as a white solid: low resolution MS (ES+ (M+H), 458; RP-HPLC (Dynamax C-8 25cm x 4.1mm; 50-90% CH3CN in H20 with 0.1% TFA buffer; 15 minutes; 2 mL/min): tr= 10.44min. <br><br> 5 Example 11 <br><br> 2-(2-Benzoyl-phenylamino)-3-{4-{2-(methyl-pyridin-2-yl-amino)-«thoxy]-phenyl)-propionic acid <br><br> A stirred solution of 300 mg (0.57 mmol) of Intermediate 21 300 mg (5.2 mmol) potassium hydroxide in 10 mL ethanol was refluxed for 30 min. The yellow solution 10 was cooled to 20 °C, 0.3 mL (5.2 mmol) acetic acid was added to the solution, then 30 mL water was added dropwise. The mixture was stirred at 20 °C for 30 min, the solid was filtered, and washed with 20 mL water three times to yield 180 mg of the title compound: low resolution MS (ESP+) m/e 496 (MH+); Anal. (CmHmNjOvI^O) Calcd. C, 71.41; H. 5.99; N, 8.33 Found C, 71.97; H, 5.98; N 15 8.33. <br><br> Example 12 <br><br> 2(SH2-benzoyl-phenylamino}-3-{4-[2-(msthyl-pyridin-2-yl-amino)-«thoxy]-phenyl}-propionic acid <br><br> 20 A solution of 1.85 g (3.63 mmol) of Intermediate 26 in 30 mL of THF, 10 mL of water, and 10 mL of MeOH at 0°C was treated with 5.45 mL (5.45 mmol, 1.5 equiv) of 1 M LiOH dropwise. After wanning to 25°C and stirring 2 h, the voiatiles were removed under reduced pressure (&lt;■ 25°C). The remaining aqueous layer was treated with EtOAc, acidified to pH 1 with 1 N HCI, and extracted with EtOAc. The combined 25 organics were concentrated in vacuo and triturated with EtOAc. Filtration gave 1.24 g of the title compound as a yellow solid. An additional 0.50 g (97% total yield) of product was obtained upon concentration of the filtrate, trituration with EtOAc, and filtration; low resolution MS (CI) m/e 518 (MNa-*-), 496 (MH-i-); Anal. (C3oH29N304'0.8H20) C, 70.65; H, 6.05; N. 8.24 Found C, 70.74; H, 6.25; N, 7.92. <br><br> 30 <br><br> Example 13 <br><br> 2-(2-B*nzoyl-phenyl2mino)-3-{4-{2-(methyl-pyridin-2-yl-amino)-flthoxy]-phenyl}-propionic acid ethyl ester <br><br> A stirred solution of 100 mg (0.19 mmol) of Intermediate 21 and 100 mg (0.65 mmol) 35 1,8-diazabicyclo[5.4.0]undec-7-ene in 5 mL toluene was refluxed for 12 h. The <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 88 <br><br> solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography using hexane/EtOAc(4:1) to yield 70 mg of the title compound: low resolution MS (ESP+) m/e 524 (MH+); TLC(hexane/EtOAc (4:1)): Rf=0.30). <br><br> 5 <br><br> Example 14 <br><br> 2-(1-Methyl-3-oxo-3-phenyl-propenylamino)-3{4-[2-(inethyl-pyridin-2-yi-amino)-ethoxy]-phenyl)-propionic acid dicyclohexylamine salt <br><br> A stirred suspension of 105 mg (0.33 mmol) of Intermediate 22, 58.5 mg (0.36 10 mmol) 1-benzoytacetone, 0.066 mL (0.33 mmol) dicyclohexylamine was refluxed for 24 h in 7 mL MeOH. 120 mL anhydrous ethanol was added to the solution, then the MeOH-ethanol mixture was distilled out from the flask at atmospheric pressure. When the remaining reaction volume was about 5 mL, the mixture was concentrated using reduced pressure. 3 mL anhydrous ether was then added to the residue at 0 15 °C, and the resulting slurry was stirred at -5-0 "C for 30 min. The solid was filtered, and washed with 5 mL cold (-50 *C) ether three times to yield 105 mg of the title compound: low resolution MS (ESP+) m/e 460 (MH-DCA+), 182 (DCAH+); Anal. (C39H52N404) Calcd. C, 73.09; H, 8.18; N, 8.74 Found C, 73.03; H, 8.13; N 8.72. <br><br> 20 The enantiomers of the 2-(1-Methyl-3-oxo-3-phenyl-propenylamino)-3{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid dicyclohexylamine salt were separated by chiral chromatography, (method: SFC, Column: Semi-Prep Chiralpak AD (25x2 cm), mobile phase. C02/Methanol (0.1% Et2NH)(75:25), flow: 5.0 mL/mr pressure: 3000 psi, inj. volume: 50 mL, temp: 40 °C, detector wavelength: 350 nM. 25 injected amount: 15 mg) to obtain 4.7 mg (S)-2-( 1 -Methyl-3-oxo-3-phenyl-propenylamino)-3{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl)-propionic acid diethylamine salt (RT: 61.5 min.) and 5.5 mg (R)-2-(1-Methyl-3-oxo-3-phenyl-propenylamino)-3{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid diethylamine salt (RT:69.8 min ): 1H NMR (CDCI3l 400 MHz) 8 11.76 (d. 1H, &gt;8.9), 30 9.46 (s(broad), 2H), 8.11 (d. 1H, &gt;4.2) 7.77 (d, 2H, &gt;7.8) 7.40 (m, 2H), 7.37 (d, 2H, &gt;7.5), 7.09 (d. 2H, &gt;8.3), 6.75 (d, 2H, &gt;8.2), 6.50 (m, 2H), 5.52 (s, 1H), 4.24 (m, 1H), 4.08 (t, 2H, &gt;5.3), 3.92 (t, 2H, &gt;5.4), 3.21 (m, 1H). 3.10 (s, 3H), 2.96 (m, 5H), 1 61 (s, 3H), 1.33 (m,6H). <br><br> 35 Example 15 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCI7EP97/00916 <br><br> 89 <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amjno)-ethoxy]-phenyl}-2-(2-benzoyl-phenylamino)-propionic acid <br><br> The title compound (24 mg) was prepared from 0.11g (0.2 mmol) of Intermediate 10 and 0.11 g (2.1 mmol) of potassium hydroxide according to the method of Example 5 11 followed by purification by reverse phase HPLC using acetonitrile/water (15% to 80% gradient over 0.5 h) as eluent: low resolution MS (FAB) m/e 536 (MH+); high resolution MS (FAB) 536.283 (MH+), C32H29N305 requires 536.2185; reverse phase HPLC tr = 21.2 min, to = 1.77 min. <br><br> 10 Example 16 <br><br> 3-{4-[2-{benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-phenylamino)-propionic acid <br><br> The title compound (209 mg) was prepared from 0.234 g (0.43 mmol) of Intermediate 10 according to the method of Example 12 followed by purification via 15 trituration with Et20/hexanes: low resolution MS (CI) m/e 558 (MNa+), 536 (MH+); Anal. (C32H29N3(V1.1H20) Calcd. C, 69.20: H, 5.66; N, 7.57 Found C, 69.45; H, 5.82; N. 7.18; TLC (EtOAc/MeOH (9:1)): Rf= 0.23. <br><br> Example 17 <br><br> 20 3-{4-[2-(Benzoxazol-2yl-methyl-amino)-ethoxy]-phenyl}-2(SH1*methyl-3-oxo-3-phenyl-propenylacnino)-propionie acid dicyclohexylamine salt <br><br> The title compound was prepared from 0.35 g (1.0 mmol) of Intermediate 8, 0.22 mL (1.1 mmol) dicyclohexylamine and 0.18 g (1.11 mmol) 1-benzoylacetone according to the method of Example 14: 1H NMR (DMSO-d6, 300 MHz) 8 11.47 (d, 1H, &gt;8.9) 25 7.84 (m. 2H), 7.45 (m, 4H), 7.31 (d, 1H, &gt;7.5). 7.18 (m, 3H), 7.03 (t, 1H, &gt;7.5), 6.86 (d. 2H, &gt;8.3), 5.60 (s, 1H). 4.25 (t, 2H. &gt;4.9), 4.07 (m. 1H). 3.91 (t, 2H, &gt;4.8), 3.26 (s, 3H), 3.14 (dd. 1H. &gt;4.3, 14.2), 3.01 (m. 2H). 2.81 (dd. 1H. &gt;8.8, 13.7), 1.99 (s, 3H), 1.80-1.05 (m, 20 H) ; low resolution MS (FAB+) m/e 500 (MH-DCA+), 182 (DCAH+). <br><br> 30 <br><br> Example 18 <br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amlno)-othoxy]-phenyl}-2(S)-[3-(3-iodo-phenyl)-1-methyl-3-oxo-propenylamino]-propionic acid dicyclohexylamine salt <br><br> The title compound (370 mg) was prepared from 0.35 g (1.0 mmol) of Intermediate 35 8. 0.22 mL (1.1 mmol) dicyclohexylamine and 0.29 g (1.0 mmol) 1-(3-iodo-phenyl)- <br><br> Printed from Miioosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 90 <br><br> butane-1,3-dione according to the method of Example 14: 1H NMR (DMSO-d6, 300 MHz) 5 11.40 (d. 1H, &gt;8.9) 7.84 (m, 2H). 7.42 (d, 1H, &gt;7.8), 7.20 (m, 4H), 7.03 (t, 1H, &gt;7.5), 6.86 (m, 3H), 5.59 (s. 1H), 4.25 (t, 2H, &gt;5.1), 4.08 (m, 1H), 3.92 (t, 2H. &gt;5.4), 3.27 (s. 3H), 3.15 (dd. iH. &gt;3.8, 13.4), 3.02 (m, 2H), 2.82 (dd, 1H, &gt;8.8, 5 13.7), 2.00 (s. 3H), 1.80-1.10 (m, 20H) ; low resolution MS (FAB+) m/e 626 (MH-DCA+), 182 (DCAH+). <br><br> Exampla 19 <br><br> 3-{4-{2-(b0nzoxazol-2-yl-m«thyl-amino)-«thoxy]-phenyl}-2-(2-benzoyl-4-methyl-10 phenylamlno)-propionic acid <br><br> The title compound (5 mg) was prepared from 0.1 Og (0.2 mmol) of Intermediate 11 according to the method of Example 11 followed by purification via reverse phase HPLC using acetonitrile/water (15% to 80% gradient ove: 0.5 h) as eluent: low resolution MS (FAB) m/e 550 (MH+); high resolution MS (r-AB) m/e 550.2349 (MH+), 15 C33H31N3O5 requires 550.2342. <br><br> Example 20 <br><br> 3-{4-{2-(banzoxazol-2-yl-methyl-amino)-«thoxy]-phenyl}-2-(2-benzoyl-4-chloro-ph«nylamino)-proplonic acid <br><br> 20 Reaction was performed behind a blast shield. To a stirred solution of 0.20 g ( 0.5 mmol) of Intermediate 9 and 0.15 g (0.6 mmol) of 2~amino-5-chloro benzophenone in 10 mL of toluene at 80°C was added 2.4 mg (5.3 mmol) of rhodium (II) acetate dimer. Nitrogen was immediately released from the reaction. The solution was heated for 2 h and then cooled to RT. Solvent was removed in vacuo. The residue 25 was purified by silica gel chromatography using EtOAc/hexane (gradient of 3:7 to 6:4)as gradient. The purified residue was then taken up in 10 mL ethanol and 0.10 g (2.0 mmol) of potassium hydroxide added. The resulting mixture was heated to 80°C for 2 h. The solution was cooled to RT and diluted with 20 mL of water. Glacial acetic acid was then added dropwise to pH 5-6. A yellow precipitate was 30 collected and washed with water and then vi ashed with hexane. The solid was dried under vacuum at 40°C for 0.5 h and further purified by silica gel chromatography using MeOH/methylene chloride (1:9) as eluent. A solid was collected which was then recrystallized from methylene chloride (containing 1% MeOH) to yield 29.7 mg of the title compound: low resolution MS (FAB) m/e 570 (MH+); Anal, calcd. for <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 91 <br><br> CajHjgNaOsCI, C, 67.43%, H, 4.95%, N, 7.37%. Found C. 67.36%, H. 4.95%, N, 7.35%. <br><br> Example 21 <br><br> 5 3-{4-(1-Benzoxazol-2-yl-pyrrolidin-3-yloxy}-phenyl]-2-(2-benzoyl-phenylamino)-propionic acid <br><br> To a stirring solution of 130 mg (0.23 mmol) of Intermediate 34 in 3 mL of dioxane and 3 mL HzO was added 10 mg (0.23 mmol, 1.0 equiv.) of lithium hydroxide. The resulting solution was stirred 12h at RT then acidified to pH2 The reaction mixture 10 was poured into 50 mL of EtOAc and washed with brine (1 X 10 mL). The organic layer was separated, dried (MgSOJ, and the solvents removed in vacuo. Purification by silica gel flash column chromatography using DCM / MeOH / HOAc 9 /1 / 0.1 as eluent afforded 127 mg of the title compound, low resolution MS (ESP) m/e 548.0 (MH+). RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 10-90% CH3CN in H20 15 with 0.1% TFA buffer; 25 minutes; 1 mL/min); tr= 13.46 min (t0= 3 min). <br><br> Example 22 <br><br> 3-{4-(1-benzoxazol-2-yl)-pyrrolidin-2R-yl-methoxy)-phenyl]-2-{2-benzoyl-phenytamino)-propionic acid <br><br> 20 The title compound (150 mg) was prepared from 0.17 g (0.30 mmol) of intermediate 31 according to the method of Example 12; low resolution MS (ES) m/e 562 (M+); TLC (EtOAc/MeOH (9:1)); Rt= 0.34 . <br><br> Example 23 <br><br> 25 3-[4-f 1 -benzoxazol-2-y l)-pyrrolidin-2S-y l-methoxy )-ph»nyl]-2-(2-benzoyl phenylamino)-propionic acid <br><br> The title compound (2.14 g) was prepared from 2.26 g (3.93 mmol) of Intermediate 30 according to the method of Example 12 followed by purification via trituration with hexanes/Et20: low resolution MS (ES) m/e 562 (M+); Anal. (C34H31N305*0.9H20) 30 Calcd. C, 70.67; H, 5.72; N. 7.27 Found C, 70.65; H, 6.01; N, 7.28. <br><br> Example 24 <br><br> 3-{4-[2-{Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-{2-cyclohexanecarbonyl-phenylamino)-propionic acid <br><br> 35 The title compound (44 mg) was prepared from 61 mg (0.11 mmol) of Intermediate 12 according tc the method of Example 21 followed by purification viasilica gel flash <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 92 <br><br> column chromatography using DCM / MeOH 9 / 1 / as eluent: low resolution MS (API) m/e 542.3 (MH+); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 10-90% CH3CN in H20 with 0.1% TFA buffer; 25 minutes; 1 mL/min); tr= 14.51 min (t0= 3 min). <br><br> 5 2? <br><br> 3-{4-{2-Benzoxazoi-2-yl-methyl-amino)-ethoxy]-ph«nyl}-2-{2-b«nzoyl-thiophen-3-ylamino)-propionic acid. <br><br> The title compound (44 mg) was prepared from 113 mg (0.20 mmol) of Intermediate 13 according to the method of Example 21 followed by purification via silica gel flash 10 column chromatography using DCM / MeOH 19 / 1 / as eluent: low resolution MS (API) m/e 542.2 (MH+). RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 10-90% CH3CN in H20 with 0.1% TFA buffer; 25 minutes; 1 mL/min); tr= 12.60 min (t0= 3 mm). <br><br> Example 29 <br><br> 15 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-benzyl-propionic acid trifluoroacetate. <br><br> To a stirring solution of 90.8 mg (0.2042 mmol) of Intermediate 15 in 2.0 mL of a 2:1 mixture of THF:H20 at rt was added 9.8 mg (0.4085 mmol, 2.0 equiv) of LiOH. The resulting solution was stirred at 60 °C for 19 h, cooled, then extracted with EtOAc. 20 The aqueous layer was acidified with 1.0 N HCI and extracted with EtOAc. The organic layers were dried (MgS04), and the solvents removed in vacuo. Purification by preparatory reverse phase HPLC using 15-80% CH3CN / HzO with 1 % TFA buffer as eluent afforded 87.3 mg of the title compound as a white amorphous solid: low resolution MS (ES) m/e 429 (M-H); high resolution MS (FAB) m/e for 25 C28H? N204: calcd. 431.1938; found 431.1965 (MH+). <br><br> Example 27 <br><br> 3-{-V-[2-|'Benzoxazol-2-yl-fnethyl-amino)-ethoxy]-phenyl}-2-(2~bromo-benzyl)-propiorJc acid trifluoroacetate. <br><br> 30 The title compound (31 mg) was prepared from 51.9 mg (0.0991 mmol) of Intermediate 16 according to the method of Example 26 followed by purification via preparatory reverse phase HPLC using 15-80% CH3CN / H20 with 1% TFA buffer as eluent: low resolution MS (ES) m/e 507 (M-H); high resolution MS (FAB) m/e for C26H26BrN204: calcd. 509.1075; found 509.1085 (MH+). <br><br> 35 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 93 <br><br> Example 28 <br><br> 3-{4-{2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2(SH(4-oxo-4H-chromene-3-csrbonyl)-aminoJ-propionic acid. <br><br> To a stirring suspension of 120 mg of 60% NaH in 10 mL of DMF at 0°C was added 5 990 mg (3.0 mmol) of N-carbobenzoxy-L- tyrosine methyl ester in 10 mL of DMF. The resulting mixture was stirred until it became clear. N-2-((N-methyl aminoethyM-methylsu!fonate)-1,3-benzoxazole 810 mg (3.0 mmol) in 10 mL of DMF was then added and mixture stirred overnight at rt Solvent was removed under reduced pressure, residue dissolved in EtOAc and washed with 1N HCI, sat NaHC03aq. and 10 water. EtOAc was evaporated providing 300 mg of yellow oil (MS (ES+)(M+H =504)). Oil was re dissolved in EtOAc 50 mg of 10% Pd/C were added and reaction mixture was hydrogenated under atm. pressure overnight. Catalyst was filtered off and solvent evaporated providing 190 mg of amino ester as yellow oil which was used without further purification. To a stirring solution of 90 mg (0.5 mmol) of 15 chrorno. s-3-carboxylic acid in 15 mL of CH2CI2 at 0°C were added several drops of DMF followed by 0.25 mL of 2M solution of oxalyl chloride in CH2CI2. The resulting solution was stirred 3 h at rt and 190 mg (0.5 mmol) of previously prepared amino ester and 50 mg (0.5 mmol) of triethylamine in 15 mL of CH:!CI2 were added and stirring continued overnight. Solvent was removed under reduced pressure and 20 residue dissolved in mixture of THF and water and 0.5 mL of 1n NaOH were added and mixture was stirred for 3 hr. 30 mg (0.5 mmol) of acetic acid were added and solvent removed under reduced pressure. Crude material was purified by RP Prep. HPLC affording 11 mg of title compound, low resolution MS(ES+)(M+H+), 528; RP-HPLC (Dynamax C-8 25cm x 4.1mm; 50-90% CH3CN in HzO with 0.1% TFA buffer; 25 15 minutes; 2 mL/min): tr= 3.20min. <br><br> Example 29 <br><br> 2(SM2-Benzoyl-phonylamino)-3-{4-[2-(5-methyl-2-phenyl'3ixazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> 30 A solution of 0.21 g (0.37 mmol) of Intermediate 35 in 20 mL of 6:4 THF:water was treated with 13 mg (0.56 mmol, 1.5 equiv) of LiOH. After stirring at RT for 3 h, TLC (Si02, 7:3 hexane:EtOAc) indicated a significant amount of starting material at Rf=0.51 and a major new component at the origin. The solution was treated with an additional 6 mg of LiOH and stirred for an additional 2 h at which point TLC indicated 35 no remaining starting material. The solution was neutralized by addition of 1 mL of <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 94 <br><br> 1N aqueous HCI arid subjected to rotary evaporation to remove THF. A yellow mixture resulted which was extracted with CHCI3 (3x20 mL). The combined extracts were washed with water (3x50 mL), dried over anhydrous MgS04, and concentrated in vacuo to afford 0.20 g (99%) of the title compound as a yellow foam: mp 85-90°C; 5 1H-NMR (DMSO-d6, 200 MHz) S 8.66 (d, 1H, &gt;7.8), 7.91 (m, 2H), 7.64-7.33 (m, 10H), 7.13 (d, 2H, &gt;8.3), 6.82 (m, 3H), 6.62 (t, 1H, &gt;7.5), 4.54 (m, 1H). 4.15 (t. 2H, &gt;6.5), 3.10 (m, 2H), 2.90 (t, 2H, &gt;6.5), 2.34 (s, 3H); low resolution MS (ES) m/e 547 (MH+); Anal. (C34H30N2O5._O.3H2O) Calcd. C, 73.98; H, 5.59; N, 5.07 Found C, 73.91; H, 5.62; N, 5.00; TLC (CH2Cl2/MeOH(95:5)): Rf=0.49. <br><br> 10 <br><br> Example 30 <br><br> 2-(2-B*nzoyl-ph«nylamino)-3-{4-{2-(4-chlorophenyl)-thiazol-4ylm«thoxy]-phenyl)-propionic acid <br><br> The title compound (154 mg) was prepared from 200 mg (0.34 mmol) of 15 Intermediate 36 according to the method of Example 12 followed by purification via trituration in acetonitriie / chloroform 1/1: low resolution MS (FAB)m / e 572 (MH++ 2), 571 (MH++ 1), 570 (MH+), 569 (M+); Anal. (C32H25CIN204S) Calcd. C, 67.54; H, 4.43; N, 4.92, Found C, 67.36; H, 4.51; N, 4.90. <br><br> 20 Example 31 <br><br> 3-{4-(2-Benzoimldazol-1-yl-ethoxy)-phenyl]-2-(2-b«nzoyl-ph«nylamino)-propionic acid <br><br> The title compound (58 mg) was prepared from 90 mg (0.17 mmol) of Intermediate 25 40 according to the method of Example 12 followed by purification via trituration with EtOAc and reverse phase MPLC purification using a C-18 column and acetonitriie / H20 3 / 2 as eluent: low resolution MS (Cl)m I e 506 (MH+), 460, 281, 145; high resolution MS (C31H27N304) Calc.506.2080, Found 506.2091. <br><br> 30 Example 32 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-&lt;5-methyl-2-(4-methoxy)-phenyl-oxazol-4-yl)-ethoxy]-phenyl}»propionic acid <br><br> To a stirring solution of 190 mg (0.32 mmol) of Intermediate 44 in 7 mL of THF / MeOH / H20 (6:0.1:1) at RT was added 0.50 mL (0.50 mmol, 1.6 equiv) of a 1.0 M <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/009H6 <br><br> 95 <br><br> solution of LiOH in HzO. The resulting solution was stirred 18 h at RT, then was poured into 50 mL of EtOAc and extracted with 1 N HCI (2 x 50 mL). The organic layer was separated, dried (MgS04), and the solvents removed in vacuo. Purification of the yellow solid by trituration in EtOAc / diethyl ether 1:1 followed by 5 vacuum filtration and drying under vacuum afforded 96 mg of the title compound as a yellow amorphous solid: low resolution MS (FAB)m / e 578 (MH ), 577 (M*); RP-HPLC (Dynamax C-8 25cm x 4.1mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 30 minutes; 1 mL/min): t = 25.59 min. <br><br> 10 Example 33 <br><br> 2(S)-(2-fc«nzoyl-phonylamino)-3-{4-[2-(5-methyl-2-(4-fluoro)-ph»nyl-oxazol-4-yl)-ethoxy]-phenyl)-propionic acid <br><br> The title compound (205 mg) was prepared from 280 mg (0.48 mmol) of Intermediate 47 and 0.73 mL (0.73 mmol, 1.5 equiv) of a 1.0 M solution of LiOH in 15 H20 according to the method ofExample 32: low resolution MS (FAB)m / e 566 (MH*), 565 (M*); Anal. ^H^FNjOs) Calcd. C, 72.33; H, 5.18; N, 4.96, Found C, 72.24; H, 5.23; N, 4.89. <br><br> Example 34 <br><br> 20 2(SH2-b®nzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(5-methyl-thien-2-yl)-oxazol-4-yl)-ethoxy]-phenyl)-propionic acid <br><br> The title compound (297 mg) was prepared from 440 mg (0.76 mmol) of Intermediate 111 and 1.10 mL (1.10 mmol, 1.5 equiv) of a 1.0 M solution of LiOH in H20 according to the method of Example 32: low resolution MS (FAB)m / e 568 25 (MH*), 567 (M*), Anal. (CaaHjoNjOjS) Calcd. C, 69.95; H, 5.34; N, 4.94, Found C, 69.31; H, 5.37; N, 4.91. <br><br> Example 35 <br><br> 2(S)-&lt;2-benzoyl-ph«nylamino)-3-{4-{2-(5-methyl-1 -phenyl-1 H-pyrazol-3-yl)-30 ethoxy]-phenyl}-propionic acid <br><br> The title compound (74 mg) was prepared from 100 mg (0.18 mmol) of Intermediate 49 and 0.27 mL (0.27 mmol, 1.5 equiv) of a 1.0 M solution of LiOH in H20 according to the method of Example 32: low resolution MS (FAB)m/e 547 (MH*), 546 (M ); t = 14.73 min.; Anal. (Cj^NjOJ Calcd. C, 74.84; H, 5.73; N, 7.70, Found C, 74.89; H, 35 5.79; N, 7.62. <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 96 <br><br> Example 36 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4~{2-(5-rnethyl-2-piperidin-1-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> 5 The title compound (47 mg) was prepared from 270 mg (0.48 mmol) of Intermediate 52 and 0.70 mL (0.70 mmol, 1.5 equiv) of a 1.0 M solution of LiOH in H20 according to the method of Example 32: low resolution MS (FAB)m /e 555 (MH ), 554 (M*); RP-HPLC (Dynamax C-8 25cm x 4.1mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 30 minutes; 1 mL/min): t = 18.54 min. <br><br> 10 <br><br> Example 37 <br><br> 2(SH2-benzoyl*phenylamino)&gt;3-(4-[2-f5-methyl-2-morpholin-4*yl-thiazol-4-yl)-ethoxy]-phenyl)-propionic acid <br><br> The title compound (456 mg) was prepared from 810 mg (1.38 mmol) of 15 Intermediate 56 and 2.00 mL (2.00 mmol, 1.5 equiv) of a 1.0 M solution of LiOH in H20 according to the method of Example 32. Purification of the yellow oil by silica gel flash column chromatography using chloroform / MeOH 12/1 as eluent followed by trituration in EtOAc / diethyl ether 1:1 provided a yellow amorphous solid: mp 148-151 °C; low resolution MS (FAB)m / e 573 (MH*), 572 (M ); Anal. 20 (C32H33N306S*HCI) Calcd. C, 63.20; H, 5.64; N, 6.91, Found C. 63 68; H, 5.70; N. 6.73. <br><br> Example <br><br> 2(SM2-benzoy!-phenyiamino)-3-{4-[2-(5-methyl-2-(4-pyridyl)-thiazol-4-yl)-25 ethoxy]-phenyl}-propionic acid <br><br> The title compound (102 mg) was prepared from 165 mg (0.29 mmol) of Intermediate 59 and 0 43 mL (0.43 mmol, 1.5 equiv) of a 1.0 M solution of LiOH in H20 according to the method of Example 32. Purification by silica gel flash column chromatography using chloroform / Me- n 9 / 1 as eluent followed by trituration in 30 EtOAc / diethyl ether 1:1 afforded a yellow amorphous solid: mp 155-158 "C; low resolution MS (FAB)m / e 564 (M+); Anal. (C33H29N304S*2HCI) Calcd. C, 62.16; H, 5.06; N, 6.59, Found C, 62.41; H, 4.82, N, 6.B3. <br><br> Example 39 <br><br> Printed from Mimosa <br><br> wr 97/31907 <br><br> PCT/EP97/00916 <br><br> 97 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(2-dimethylamino-5-methyl--thiazol-4-yl)-ethoxy]-phenyl)-propionic acid <br><br> To a stirring solution of 150 mg (0.27 mmol) of Intermediate 62 in 7 mL of THF / MeOH / H20 (6:0.1:1) at RT was added 0.42 mL (0.42 mmol, 1.5 equiv) of a 1.0 M 5 solution of LiOH in H20. The resulting solution was stirred 5 h at RT, then the solvent was removed in vacuo. The residue was redissolved in THF and acidified with 0.022 mL (0.42 mmol, 1.5 equiv) of concentrated sulfuric acid. Purification of the yellow oil by silica gel flash column chromatography using EtOAc / MeOH 1 /1 with 1% ammonium hydroxide as eluent afforded 39 mg of the title compound as a 10 yellow amorphous solid: low resolution MS (FAB)m / e 531 (MH ), 530 (M ); Anal. (C3oH„N304S- H20) Calcd. C, 65.79; H, 6.07; N, 7.67, Found C. 65.74; H, 5.87; N, 7.54. <br><br> Example 40 <br><br> 15 2(S)-(2-bflnzoyl-phenylamino)-3-{4-{2-(5-methyl-2-(5-methyl-isoxazol-3-yl)-thiazol-4-yl)-«thoxy]-phenyl}-propionic acid <br><br> The title compound (220 mg) was prepared from 450 mg (0.77 mmol) of Intermediate 66 and 1.20 mL (1.2 mmol, 1.5 equiv) cf a 1.0 M solution of LiOH in H20 according to the method of Example 32. Purification by silica gel flash column 20 chromatography using chloroform / MeOH 9 /1 as eluent followed by trituration with diethyl ether afforded a yellow amorphous solid: low resolution MS (FAB)m / e 568 (MH+); Anal. (CazH^NjOsS* HzO) Calcd. C, 65.62; H, 5.34; N, 7.17, Found C. 65.64; H. 5.13; N, 7.13. <br><br> 25 Example 41 <br><br> 2(SH2-benzoyl-phenylamino)-3-(4-{2-{5-methyl-2-(4-methyl[1,2,3]thiadiazol-5-yl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid <br><br> The title compound (120 mg) was prepared from 230 mg (0.38 mmol) of Intermediate 69 and 0.575 mL (0.58 mmol, 1.5 equiv) of a 1.0 M solution of LiOH in 30 H20 according to the method of Example 32. Purification by silica gel flash column chromatography using chloroform / MeOH 9 / 1 as eluent afforded a yellow amorphous solid: low resolution MS (FAB)n?/e 585 (MH ); RP-HPLC (Dynamax C-8 25cm x 4.1mm; 50-100% CH3CN in HzO with 0.1% TFA buffer, 30 minutes; 1 <br><br> mL/min). t= 16.52 min. <br><br> 35 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 98 <br><br> Example 42 <br><br> 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-methyl-2-(4-methyl-piperazin-1-yl)-thiazoM-y(]-ethoxy&gt;-phertyi)-propionic acid <br><br> A suspension of 1.93 g (7.40 mmol, 1.10 equiv) of triphenylphosphine, 2.51 g (6.70 5 mmol) of Intermediate 23, and 2.20 g (6.70 mmol) of Intermediate 71 in 40 mL of dry toluene was heated to 95 °C for 15 min to effect dissolution of intermediate 23 to provide a clear yellow solution. To this solution was added 1.23 g (7.04 mmol, 1.05 equiv) of diethyl azodicarboxylate dropwise over 10 min. The reaction was then allowed to cool to RT and stirred 16 h. The toluene was removed in vacuo, and the 10 residue was purified by silica gel flash column chromatography using EtOAc / MeOH 10/1 with 1% ammonium hydroxide as eluent to afford 3.06 g of the title compound as a yellow oil. Approximately 130 mg of the material was dissolved in diethyl ether and the pH was adjusted to 1.0 by the addition of a 1.0 M solution of HCI in diethyl ether. The resulting yellow precipitate was filtered and dried under vacuum to afford 15 100 mg of the HCI salt: low resolution MS (FAB)m / s 589 (MH+); RP-HPLC (Dynamax C-8 25cm x 4.1mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 30 minute mL/min): t= 17.79 min. <br><br> Example 43 <br><br> 20 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[2-(3-dim®thylamino-propylamino)-5-methyl-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid <br><br> The title compound (522 mg) was prepared from 695 mg (1.15 mmol) of Intermediate 74 and 1.75 mL (1.75 mmol, 1.5 equiv) of a 1.0 M solution of LiOH in H2f ccording to the method of Example 32. Purification by silica gel flash column <br><br> 25 ch atography using MeOH as eluent followed by trituration with EtOAc afforded a <br><br> + <br><br> yellow amorphous solid: low resolution MS (FAB)m / e 587 (MH ); Anal. (CaaHjaN^S'HCI'HjO) Calcd. C, 61.81; H, 6.44; N, 8.73, Found C. 61.93; H, 6.20; N. 8.77. <br><br> 30 Example 44 <br><br> 2(S)-(2-benzoyl-phenyiamino)-3-(4-{2-[2-(2-methoxy-ethylamino)'5-methyl-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid <br><br> The title compound v473 mg) was prepared from 907 mg (1.58 mmol) of Intermediate 76 and 12.40 mL (2.40 mmol, 1.5 equiv) of a 1.0 M solution of LiOH in 35 H20 according to the method of Example 32. Purification by silica gel flash column <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 99 <br><br> chromatography using chloroform / MeOH 9 / 1 as eluent afforded a yellow <br><br> ♦ <br><br> amorphous solid: low resolution MS (FAB)m / e 560 (M ); Anal. (C^HaaNjOgS'HOHaO) Calcd. C, 60.63; H, 5.91; N, 6.84, Found C, 60.61; H, 5.55; N. 6.83. <br><br> 5 <br><br> Example 45 <br><br> 2-{1-Carboxy-2-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl)-ethylamino)-benzoic acid mathyl ester <br><br> The title compound (290 mg) was prepared from 400 mg (0.75 mmol) of 10 Intermediate 150 and 1.50 mL (1.50 mmol, 2.0 equiv) of a 1.0 M solution of LiOH in H20 according to the method of Example 32. Purification by silica gel flash column chromatography using chloroform / MeOK 9 /1 as eluent afforded a white solid: low resolution MS (FAB)m / e 517 (M ); Anal. (C29H28N2OsS »H20) Calcd. C, 65.15; H, 5.65; N, 5.24, Found C, 65.60; H, 5.35; N, 5.23. <br><br> 15 <br><br> Example 46 <br><br> 2-(1-Carboxy-2-{4-[2-(4-clhorophenylsulfanyl)-ethoxy]-phenyl}-ethylamino)-benzoic acid methyl ester <br><br> The title compound (40 mg) was prepared from 118 mg (0.24 mmol) of Intermediate 20 151 and 0.47 mL (0.47 mmol, 2.0 equiv) of a 1.0 M solution of LiOH in H20 according to the method of Example 32. Purification by silica gel flash column chromatography using chloroform / MeOH 9 /1 as eluent afforded a light tan solid: low resolution MS (FAB)m /e 486 (M ); RP-HPLC (Dynamax C-8 25cm x 4.1mm, 50-100% CHjCN in HzO with 0.1% TFA buffer; 30 minutes; 1 mL/min): t = 16.81 <br><br> 25 min. <br><br> Example 47 <br><br> 2-{1-Carboxy-2-[4-(1-phenyl-pyrrolidin-2-ylmethoxy)-phenyl]-ethylamino) benzoic acid methyl ester <br><br> 30 A suspension of 95 mg (0.36 mmol, 1.10 equiv) of triphenylphosphine, 100 mg (0.30 mmol) of Intermediate 127, and 80 mg (0.36 mmol) of (SH-)-1-(4-nitrophenyl)-2-pyrrolidineMeOH in 5 mL of dry toluene was heated to 80 °C for 15 min to effect dissolution of Intermediate 127 to provide a clear yellow solution. To this solution was added 68 mg (0.33 mmol, 1.2 equiv) of diisopropyl azodicarboxylate dropwise 35 over 5 min. The reaction was then allowed to cool to RT and stirred 16 h. The <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 100 <br><br> toluene was removed in vacuo, and then the residue was stirred vigorously for 1 h in 10 mL of 1:1 diethyl ether /1 N LiOH biphasic solution to effect selective removal of residual Intermediate 127. The layers were separated and the organic layer washed with H20, dried (MgS04), and solvent removed in vacuo. The material was purified 5 by silica gel flash column chromatography using hexane / EtOAc 3 / 1 as eluent to afford 94 mg of the title compound as a yellow solid. This material was dissolved in 5 mL of THF / MeOH / H20 (4:0.1:1) at RT and 0.35 mL (0.35 mmol, 2.0 equiv) of a 1.0 M solution of LiOH in H20 was added. The resulting solution was stirred 4 h at RT, then was poured into 20 mL of EtOAc and extracted with 1 N HCI (2x10 mL). 10 The organic layer was separated, dried (MgS04), and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using chloroform / MeOH 9 / 1 as eluent afforded 30 mg of the title compound as a yellow solid: low resolution MS (FAB)m/e 520 (MH ); Anal. (C28H29N307 *H20) Calcd. C. 62 56; H, 5.81; N. 7.82, Found C. 62.18; H, 5.50; N. 7.86. <br><br> 15 <br><br> mpfr 48 <br><br> 3-{4-[2-(BanzoxKol-2-yl-m«thyl-amino)-ethoxy]-phenyl}-2-(2-cyclopentanecarbonyl-phenylamino)-propionic acid <br><br> The title compound (66 mg) was prepared from 0.55 g (1.07 mmol) of Intermediate 20 77 and 67.5 mg (1.61 mmol, 1.5 equiv.) of lithium hydroxide according to the method of Example 32 followed by purification via silica gel flash column chromatography using DCM / MeOH 98 / 2 as eluent: low resolution MS (ES) m/e 526.2 (MH ); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 minutes; 1 mL/min); t,= 21.29 min (to= 3 min). <br><br> 25 <br><br> Example 49 <br><br> 3-{4-[2-(BenzoxazoU2-yl-niathyl-amino)-ethoxy]-ph*nyl}-2-(2-cycloheptanecarbonyl-phenylaminol-propionic acid <br><br> The title compound (39 mg) was prepared from 0.13 g (0.23 mmol) of Intermediate 30 78 and 14.5 mg (0.35 mmol, 1.5 equiv.) of lithium hydroxide according to the method of Example 32 followed by purification via silica gel flash coli'mn chromatography using DCM / MeOH 98 / 2 to 90 /10 as eluent: low resolution MS (ES) m/e 554.1 (MH ); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 minutes; 1 mL/min); t,= 24.86 min (t0= 3 min). <br><br> 35 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 101 <br><br> Example SO <br><br> 3-{4-[2-{B»nzoxazol-2-yl-methyl-a'nino)-ethoxy]-phenyl}-?-(2-cyc)ohexan«carbonyl-5-fluoro-phenylamino)-propionic acid The title compound (139 rrg) was prepared from 0.39 g (0.68 mmol) of Intermediate 5 79 and 34.4 mg (0.82 mmol, 1.2 equiv.) of lithium hy roxide according to the method of Example 32 followed by purification via silica gel flash column chromatography using DCM / MeOH 98 / 2. to 95 / 5 as eluent. low resolution MS (ES) m/e 558.0 (MH); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 minutes; 1 mL/min); t,= 22.62 min (to= 3 min). <br><br> 10 <br><br> Example 51 <br><br> 3-{4-[2-(B®nzoxazol-2-yl-methyl-amino)-ethoxy]-ph«nyl}-2-(4-cyclohexan®carbonyl-2-methyl-2H-pyraizol-3-ylamino)-propionic acid <br><br> 15 The title compound (68 mg) was prepared from 0.175 g (0.31 mmol) of Intermediate <br><br> 80 and 16 mg (0.37 mmol, 1.2 equiv.) of lithium hydroxide according to the method of Example 32 followed by purification via silica gel flash column chromatography using DCM I MeOH 98 / 2 to 90 / 10/ 0.1 DCM / MeOH/ HOAc as eluent low resolution MS (ES) m/e 544.1 (MH); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 30- <br><br> 20 80% CH3CN in H20 with 0.1% TFA buffer, 25 minutes, 1 mL/min); t,= 14.66 min (to= 3 min). <br><br> Example 52 <br><br> 3-{4-[2-(Benzoxazol-2-yl-m0thyl-amino)-ethoxy]-phenyl}-2-(3-benzoyl-25 thipph«n«-2-ylamino)-propionic acid <br><br> The title compound (77 mg) was prepared from 0.145 g (0.26 mmol) of Intermediate <br><br> 81 and 14 mg (0.34 mmol, 1.3 equiv.) of lithium hydroxide according to the method of Example 32 follow?by purification via silica gel flash column chromatography using DCM /MeOH 95 / 5 to 90 /10 as eluent: low resolution MS (ES) m/e 539.9 <br><br> 30 (MH ); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 minutes; 1 mL/min); tr= 18.16 min (to= 3 min). <br><br> Example 53 <br><br> 2-(2-Cyclohexanecarbonyl-phenylamino)-3-{4-{2-(5-niethyl-2-ph»nyl-cx^zol-4-35 yl)-ethoxy]-pheriyl}-propiontc acid <br><br> Printed frorr. Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 102 <br><br> The title compound (750 mg) was prepared from 1.08 g (1.90 mmol) of enantiomer 1 of intermediate 83 and 120 mg (2.66 mmol, 1.5 equiv.) of lithium hydroxide according to the method of Example 32 followed by purification via silica gel flash column chromatography using DCM / MeOH 95 / 5 as eluent: low resolution MS 5 (ES) m/e 551.2 (MH); RP-HPLC (Vydac C-18. 25 cm x 4.6mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 minutes; 1 mL/min); tr= 18.22 min (to= 3 min). Daicet Chiral OD-H (4.6 X 250 mm, 5m; 0.7 mL/min; inj volume 3mL, UV 230 nM; 60/ 40 IPA/ Hexane; 30 min); t,= 7.44 min, 99.99 % ee. <br><br> 10 Example 54 <br><br> 2-(2-Cyclohexanecarbonyl-phenylamino)-3-(4-[2-(5-niethy)-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> The title compound (78 mg) was prepared from 220 mg (0.39 mmol) of enantiomer 2 of Intermediate 83 and 24 mg (0.58 mmol, 1.5 equiv.) of lithium hydroxide according 15 to the method cf Example 32 followed by purification via silica gel flash column chromatography using DCM / MeOH 95 / 5 as eluent: MS.HPLC identical to Example 53. Daicel Chiral OD-H (4.6 X 250 mm, 5m; 0.7 mL/min; inj volume 3mL, UV 230 nM; 60/ 40 IPA/ Hexane; 30 min); tr= 11.67 min, 99.3 % ee. <br><br> 20 Example 55 <br><br> 3-{4-(1-Benzoxazol-2-yl-pyrroiidin-3-yloxy)-phenyl]-2-(2-b»nzoyl-phenyl«mino)-propionic acid <br><br> The title compound (115 mg) was prepared from 200 mg (0.36 mmol) of 3-[4-(1-Benzoxazo!-2-yl-pyrrolidin-3-yloxy)-phenyl]-2-(2-benzoyl-phenytamino)-propionic 25 acid methyl ester and 18 mg (0.43 mmol, 1.2 equiv.) of lithium hydroxide according to the method of Example 32 followed by purification via silica gel flash column chromatography using DCM / MeOH 90 /10 as eluent: low resolution MS (ES) m/e 546.0 (MH ); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 30-80% CHjCN in H20 with 0.1% TFA buffer; 25 minutes; 1 mL/min); t = 17.92 min (to= 3 min). Daicel Chiral OD-30 H (4.8 X 250 mm, 5m; 0.7 mL/min; inj volume 3&gt;nL, UV 230 nM; 40/ 80/ 0.1 IPA/ Hexane/ TEA; 30 min); tr= 6.8 min and 10.0 min. <br><br> Example 56 <br><br> 3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl)-2(S)-[2-(pyridine-4-35 carbonyl)-phenylamino]-propionic acid <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 103 <br><br> The title compound (815 mg) was prepared from 1.71 g (3.05 mmol) of Intermediate <br><br> 87 and 192 mg (4.57 mmol, 1.5 equiv.) of lithium hydroxide according to the method of Example 32 followed by trituration in DCM: low resolution MS (ES) m/e 546 (MH ); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 30-80% C,H3CN in H20 with 0.1% TFA <br><br> 5 buffer, 25 minutes; 1 mL/min); tr= 16.35 min (t0= 3 min). Daicel Chiral OD-H (4.6 X 250 mm, 5m; 0.7 mL/inin; inj volume 3mL, UV 230 nM; 40/ 60/ 0.1 IPA/ Hexane/ TEA; 30 min); tr= 9.21 min, 96%ee. <br><br> Example 57 <br><br> 10 3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2(S)-{2-(pyridineN-oxid»-4-carbonyl)-phenylamino]-propionic acid <br><br> The title compound (52 mg) was prepared from 70 mg (0.12 mmol) of Intermediate <br><br> 88 and 10 mg (0.24 mmol, 2 equiv.) of lithium hydroxide according to the method of Example 32 followed by purification via silica gel flash column chromatography using <br><br> 15 DCM / MeOH 90 / 10 as eluent. 1H NMR (DMSO-d6 400MHz) s 8.69 (d,iH, J= 7.2), 8.26 (d, 2H. J= 7.1), 7.85 (m, 3H), 7.46 (m, 4H), 7.38 (m, 2H), 7.05 (d, 2H, J= 8.4), 6.74 (m, 2H), 6.49 (m, 1H), 4.10 (m, 2H), 3.15 (m, 2H), 2.96 (m, 1H), 2.85 (m, 2H), 2.49 (s, 3H); low resolution MS (ES) m/e 562 (MH ); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 minutes; 1 mL/min); t,= 20 15.92 min (to= 3 min). <br><br> Example 58 <br><br> 3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-ph»nyl}-2(S)-[2-(pyridine^-carbonyl)-phenyiamino]-propionic acid <br><br> 25 The title compound (506 mg) was prepared from 0.54 g (0.96 mmol) of Intermediate <br><br> 89 and 122 mg (2.88 mmol, 3.0 equiv.) of lithium hydroxide according to the method of Example 32 followed by purification via silica gel flash column chromatography using DCM/ MeOH 90/ 10 as eluent: low resolution MS (ES) m/e 546 (MH); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; <br><br> 30 25 minutes; 1 mL/min); t = 17.31 min (to= 3 min). Daicel Chiral OD-H (4.6 X 250 mm, 5m; 0.7 mL/min; inj volume 3mL, UV 230 nM; 40/ 60/ 0.1 IPA/ Hexane/ TEA; 30 min); tr= 8.98 min, 78 %ee. <br><br> Example 59 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 104 <br><br> 3-{4-[2-x5-mftthyl-2-phonyl-oxazol-4-yl)-ethoxy]-phenyl}-2(S)-[2-&lt;pyridine-N-oxlde-3-carbonyl)-phenylamino]-propionic acid <br><br> To Intermediate 89 (100 mg, 0.18 mmol) in DCM (5 mL) at RT was added mCPBA (57 mg, 0.33 mmol, 1.5 equiv). After 24h a second 1.5 equiv mCPBA was added. 5 The reaction mixture stirred 2h, was concentrated to dryness and purified by silica gel flash column chromatography using DCM / MeOH 95 / 5 as eluent afforded 50 mg of the intermediate N-oxide: low resolution MS (ES) m/e 578.3 (MH ). Hydrolysis according to the method of Example 32 followed by purification via silica gel flash column chromatography using DCM / MeOH 90 /10 as eluent afforded 20 10 mg of the title compound: low resolution MS (ES) m/e 562 (MH ); RP-HPLC (Vydac C-18, 25 cm x 4.6mm; 30-80% CH3CN in H20 with 0.1% TFA buffer; 25 minutes; 1 mL/min); t,= 15.70 min (to= 3 min). <br><br> Example 60 <br><br> 15 2S-(2-benzoyl-phenylamino)-3-(4-[2-(5-methyl-3-phenyl-pyrazol-1 -yl)-ethoxy]-phenyl&gt;-propionic acid <br><br> The title compound (77 mg) was prepared from 110 mg (0.20 mmol) of Intermediate 91 and 0.295 mL (0.295 mmol) of 1 M LiOH according to the method of Example 32 followed by purification via silica gel flash column chromatography eluting with 20 chloroform/MeOH (9:1) and trituration with Et20/hexanes: low resolution MS (ES) m/e 546 (MH ); Anal. (C34H31N304.1.2H20) Calcd. C, 71.99; H, 5.94; N, 7.41 Found C. 71.96; H, 5.85; N. 7.33; RP-HPLC (C-18, 4.6mm x 25cm; 50-100% CH3CN in HjO with 0.1% TFA; 30 minutes; 1 mL/min): tr= 14.5 min (t„= 3 min). <br><br> 25 Example 61 <br><br> 2S-(2-benzoyl-phenylamino)-3-[4-{1-pyridin-2-yl-pyrrolidin-2S-yl-m9thoxy)-phenyQ-propionic acid <br><br> The title compound (1.17 g) was prepared from 1.2 g (2.24 mmol) of Intermediate 93 and 3.4 mL (3.4 mmol) of 1 N LiOH according to the method of Example 32 followed 30 by purification via trituration with CHCl3/Et20: low resolution MS (ES) m/e 522 (M ); Anal. (C32H31N304»HCI«0.6H20) Calcd. C, 67.56: H, 5.88; N, 7.39; CI, 6.23 Found C, 67.57; H, 5.87; N, 7.31; CI, 6.46. <br><br> Example 62 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 105 <br><br> PCT/EP97/00916 <br><br> 2S-{2-benzoyl-phenylamino)-3-{4-[2-&lt;1-methyl-4-phenyl-1H-imidazol-2-yl)-ethoxy]-phenyl}-propionic acid <br><br> The title compound (70 mg) was prepared from 83 mg (0.15 mmol) of Intermediate 95 and 0.223 mL (0.223 mmol) of 1 N LiOH according to the method of Example 32 5 followed by purification via trituration with EtOAc. low resolution MS (ES) m/e 546 (MH*); Anal. (C34H31N304-HCK).5H20) Calcd. C, 65.09; H, 5.63; N. 7.11; CI. 6.00 Found C, 69.08; H. 5.63; N, 7.04; CI, 6.04. <br><br> Example 63 <br><br> 10 2S-(2-b«nioy l-pheny lamino)-3-(4-[2-v.&gt;-furan-2-y l-5-methyl-pyrazol-1 -yl)-ethoxy]-phenyl)-proplonic acid <br><br> A solution of 239 mg (0.911 mmol) of triphenylphosphine in 1.8 mL of anhydrous THF at 0°C was treated with 0.143 mL (0.911 mmol) of DEAD in a dropwise fashion. After stirring for 10 min, the mixture was added to a solution of 342 mc* (0.911 mmol) 15 of Intermediate 23 and 175 mg (0.911 mmol) of Intermediate 97 in 1.8 mL of anhydrous THF at 25°C. The reaction was stirred at 25°C for 15 h then concentrated in vacuo (@&lt;25°C). The residue was purified by. silica gel flash column chromatography using EtOAc/hexanes (1:1) as eluent to give impure intermediate ester. The crude ester was hydrolyzed according to the method of 20 Example 32 followed by purification via silica gel flash column chromatography using CHCIj/MeOH (9:1) as eluent followed by trituration with Et20 to afford 180 mg (37%) of the title compound as a yellow solid: low resolution MS (ES) m/e 558 (MNa ), 536 (MH*); Anal. (C32H29N305'1.2H20) Calcd. C. 68.98; H. 5.68; N. 7.54 Found C. 68.65; H. 5.29; N. 7.76; TLC (CHCI3/MeOH (9:1)): R,= 0.24. <br><br> 25 <br><br> Example 64 <br><br> 2S-(2-b«nzoyl-phenylamino)-3-{4-[2-{5-methyl-3-phenyl-[1,2,4]triazoM-yl)-athoxy]-phanyl}'propionic acid <br><br> The title compound (141 mg) was prepared from 180 mg (0.32 mmol) of 30 Intermediate 99 and 0.482 mL (0.482 mmol) of 1 N LiOH according to the method of Example 32 followed by purification via trituration with EtzO: low resolution MS (ES) m/e 569 (MNa*), 547 (MH*); Anal. (CmHjqN^O.IHjO) Calcd. C. 70.20; H, 5.71; N, 9.92 Found C, 70.35; H. 5.70, N, 9.98; TLC (CHCI3/MsOH (9:1)): Rf= 0.25. <br><br> 35 Example 65 <br><br> Printed trom Kimosa <br><br> WO 97/31907 <br><br> PCT/F.P97/00916 <br><br> 106 <br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(3-methoxymethyl-5-mathyl-2-ph0nyl-3H-imidazol-4-yl}-ethoxy]-phenyl}-propionic acid <br><br> The title compound (324 mg) was prepared from 340 mg (0.56 mmol) of Intermediate 102 and 0.845 mL (0.845 mmol) of 1 N LiOH according to the method 5 of Example 32 followed by purification via trituration with EtzO: low resolution MS (ES) m/e 612 (MNa ), 590 (MH*); Anal. (CaeHjsNaOs'O.SHjO) Calcd. C, 68.47; H, 5.84; N, 6.65 Found C, 68.46; H. 6.14; N. 6.41; TLC (CHCI3/MeOH (9:1)): Rf 0.20. <br><br> Examola 66 <br><br> 10 2S-&lt;2-banzoyl-phanylamino)-3-{4-[2-(6-mathyl-2-phenyl-3H imldazol-4-yl)-ethoxy]-phenyl)-propionic acid hydrochloride salt <br><br> The title compound (162 mg) was prepared from 200 mg (0.36 mmol) of Intermediate 104 and 0.536 mL (0.536 mmol) of 1 N LiOH according to the method of Example 32 followed by purification via trituration with EtOAc/EtzO: low resolution 15 MS (ES) m/e 546 (MH*); Anal. (CMH31N304*1.0H20) Calcd. C, 68.05; H. 5.71; N, 7.00; CI. 5.91 Found C, 68.03; H, 5.74; N. 6.94, CI, 5.98 <br><br> Example 67 <br><br> 2S-&lt;2-benzoyl-phonylamino)-3-{4-[2-(5-methyl-2-phenyl-thJazo(-4-yi)-«thoxy]-20 phenyty-propionic acid <br><br> The title compound (283 mg) was prepared from 350 mg (0.61 mmol) of Intermediate 107 and 0.91 mL (0.91 mmol) of 1.0 N LiOH according to the method of Example 32 followed by purification via trituration with Et20/hexanes: low resolution MS (ES) m/e 586 (MNa*), 563 (M*); Anal. (C^H^N^S-OS^O) Calcd. C. 71.89; H, 25 5.43; N, 4.93; S, 5.64 Found C, 71.91; H, 5.44; N. 4.93; S. 5.62. <br><br> Example 68 <br><br> 2(SH2-benzoyl-phenylamino)-3-&lt;4-[2-{5-methyl-2-(3-methyl-thlen-2-yl)-oxazoi-4-yl)-sthoxy]-phanyl}-propionic acid <br><br> 30 The title compound (90 mg) was prepared from 100 mg (0.17 mmol) of Intermediate 112 and 10.8 mg (0.258 mmol, 1.5 equiv) of LiOH according to the method of Example 32: MS (ES-) m/e 565.0 (MH-), Anal. (C33H30N2O5S 0.4 EtOAc) Calc C, 69.04; H, 5.56; N, 4.65; Found O. 69.45; H, 5.95; N. 4.33. <br><br> 35 Example 69 <br><br> I'r i nf a&lt;l 1 r'M t it. <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 107 <br><br> 2(S'H2-{4-[2-{5-nitro-2-pyridyloxy)-«thoxy]-phenyl}-1-metho*ycarbonyl-•thylamino)-benzoic acid <br><br> A solution of 109 mg (0.220 mmol) of Intermediate 152 in THF (2 mL) and EtOH (2 mL) was treated with 1M LiOH (1 mL). The reaction was stirred for 45 min. Water (10 5 mL) and 1N HCI (1 mL) were added. The reaction was extracted with EtOAc (2 x 30 mL). The combined organics were washed with brine (1 x 30 mL), dried over MgS04, filtered and concentrated. The material was purified by flash chromatography using EtOAc + 0.1% AcOH as eluent to afford 25 mg (24%) of the title compound: H NMR (CDCI3 400 MHz) 6 9.07 (d, 1H, J = 2.7), 8.36 (dd. 1H, J= 2.8, 6.3), 7.91 ( dd, 1H. J 10 = 1.6, 6.3), 7.35 (t, 1H J = 7.4), 7.20 (d, 2H, J = 8.7), 6.88 ( dd. 3H, J = 2.7, 7.7), 6.68 (t, 1H. J = 7.4), 6.58 (d, 1H, J= 8.3), 4.77 (t, 2H. J = 4.6). 4.32 (m. 3H). 3.86 (s, 3H). 3.20 ( ddd, 2H, J = 5.1, 7.7, 7.7); low resolution MS m/e 480 (MH-). <br><br> Example 70 <br><br> 15 2(S)-{2-(4-[2-(5-chloro-2-pyridylsuffanyl)-ethoxy]-ph«nyl}-1 -methoxycarbonyl-•thylamino)-benzoic acid <br><br> The title compound (90 mg) was prepared from 155 mg (0.310 mmol) of Intermediate 153 according to the method of Example 69: H NMR (COCl3 400 MHz) 5 8.38 (d. 1H, J = 2.4). 8.19 (d, 1H. J = 5.9). 7.91 (d. 1H. J = 8.1), 7.46 (dd. 1H, 20 J = 2.5, 7), 7.34 (t, 1H, J = 7.1), 7.19 (d, 2H. J = 8.5), 7.13 (d, 1H. J = 8.6), 6.87 (d. 2H, J =7.5 ). 6.67 (t. 1H, J =7.5), 6 57 (d. 1H. J = 8.4), 4.30 (m. 1H). 4.18 (t, 2H. J = 6.8), 3.85 (s. 3H). 3.52 (t. 2H, J = 6.8), 3.18 (ddd, 2H, J = 5.1. 7.5, 7.5); low resolution MS m/e 485 (MH-), 486 (M). <br><br> 25 Example 71 <br><br> 2(S)-(2-{4-{2-&lt;N-ethyl-2-methyi-toluidino)-ethoxy]-phenyl}-1-methoxycarbonyl - <br><br> ethylamino)-b«nzoic acid <br><br> The title compound (16 mg) was prepared from 90 mg (0.184 mmol) of Intermediate 154 according to the method of Example 69: H NMR (CDCI3 400 MHz) S 8.19 (s 30 1H). 7.91 (d. 1H. J = 6.7), 7.33 (t. 1H. J= 8.4), 7.18 (d, 2H, J = 7.9), 7.11 (m. 1H), 6.82 (m, 1H), 6.67 (t. 2H, J = 8.5), 6.56 (d. 2H, J = 8.4), 6.53 (m. 1H), 4.30 (q. 1H. J = 6.9), 4.07 (m, 2H). 3.85 (s, 3H), 3.69 (m. 2H), 3.43 (m, 2H), 3.21 (ddd. 2H, J= 5.3, 7.7, 7.7), 1.2 (m, 3H); low resolution MS m/e 475 (MH-), 476 (M). <br><br> 35 Example 72 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 108 <br><br> 3-[4-(3-Banzoxazol-2-yl-thiazolidin-4(R)-ylmethoxy)-phanyl]-2{S)-{2-benzoyl-phanylamino)-propionic acid <br><br> A solution of 0100 mg (0.168 mmol) of Intermediate 116 dissolved in 5 mL of 2/2/1 (v/v) acetonitrile/MeOH/water was treated with 17.5 mg (0.337 mmol) of LiOH H20 5 for 2 h at room temperature. The reaction was quenched with an excess of citric acid, voiatiles evaporated off and the product partitioned between EtOAc and water. The organics were then combined, dried and the solid residue left after rotary evaporation was further purified on preparative C18HPLC to afford 50 mg of the title compound: TLC: R,=0.41 (chloroform / MeOH 9 / 1); MS (ES+) m/e 580 (M+1); 10 Anal. (C33H29N305S2TFA) Calc. C, 55.02; H. 3.87; N, 5.20; S, 3.97, Found C, 54.38; H, 3.90; N. 5.19; S 3.91. <br><br> Example 73 <br><br> 3-{4-[2-{ben;Eoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(4-trifluoromethyl-15 bensoyl)-phenylamino-proplonic acid <br><br> A solution of Intermediate 113 (250 mg, 0.44 mmol), K2C03, (182 mg. 1.3 mmol), Pd(CI) 2(PPh3) 2 (9.2 rrg, 0.013 mmol) and 4-trifluoromethylbenzene boronic acid (91.4 mg, 0.48 mmol) in dioxane (4.4 mL) was stirred under CO (1 atm, balloon) at 100° for 20 h. The resulting brown heterogeneous mixture was partitioned between 20 water (50 mL) and EtOAc (50 mL). The EtOAc solution was washed with 2.0 M NaOH and brine (25 mL each), dried over MgS04 and concentrated to a brown oil. This material was chromatographed on silica gel (75 g) with EtOAc/nexane 1/2 as eluent to afford 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy)-phenyl}-2-{2-(4-trifluoromethyl-benzoy()-phenylamino-propionic acid methyl ester (206.9 mg, 76%) 25 as a yellow oil: low resolution MS (ES") m/e 618 (MH*); TLC (EtOAc/hexane, (1/1)): Rf= 0.51. A solution of the methyl ester (206.9 mg, 0.335 mmol) in THF/EtOH/I.O M LiOH (3/1/1, 5 mL) was hydrolyzed foloowing the conditions outlined in Example 32 to afford the title compound (175 mg, 86%) as a yellow solid: mp 177-178 °C; low resolution MS (ES*) m/e 604 (MH+); Anal. Calc. for C33H28 F3N3051.0 H20: C, 30 63.76; H, 4.86; N, 6.76; Found: C. 63.44; H, 4.71; N, 6.52 <br><br> Example 74 <br><br> 3-{4-[2-(benzoxazoi-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(2-thiophenecarbonyl)-phenylamino-propionic acid <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 109 <br><br> Using the protocol reported for Example 73, the title compound was synthesized from Intermediate 113 and 2-thiophene boronic acid in 27% overall yield and isolated as a yellow solid, mp 76-80 "C; low resolution MS (ES+) m/e 542 (MH*);high resolution MS (FAB*) Calc. for C30H27N3O5S, (MH*): 542.1750; Found; 542.1750. <br><br> 5 <br><br> Example 75 <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(3-thiophenecarbonyl}~phenylamino-propionic acitf <br><br> Using the protocol reported for Example 73, the title compound was synthesized 10 from Intermediate 113 and 3-thiophenene boronic acid in 28% overall yield and isolated as a yellow solid: mp 85-95 °C, low resolution MS (ES*) m/e 542 (MH*); Anal. Calc. for CaoH^NaOjS, 1.5H20: C, 63.37; H, 5.32; N, 7.39; Found: C, 63.48; H. 4.97; N. 7.08. <br><br> 15 Example 76 <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy}-phenyl}-2-[2-{3-trif)uoroimethylbenzoyl)-phenylamino-propionic acid <br><br> Using the protocol reported for Example 73, the title compound was synthesized from Intermediate 113 and 3-trifluorobenzene boronic acid in 63% overall yield and 20 isolated as a yellow solid, mp 159-160 "C; low resolution MS (ES*) m/e 604 (MH*); Anal. Calc. for C33H28F3N3050.5H20: C, 64 70; H, 4.77. N, 6.86; Found: C, 64.77H, 4.75; N, 6.83. <br><br> Example 77 <br><br> 25 3-{4-[2~(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(2-trifluoromethyl-benzoyl)-phenylamino-propionic acid <br><br> Using the protocol reported for Example 73, the title compound was synthesized from Intermediate 113 and 2-trrfluoromethylbenzene boronic acid in 70% overall yield and isolated as a yellow solid: mp 102-106 "C; low resolution MS (ES*) m/e 604 30 (MH*); Anal. Calc. for C33H2aF3N305 1.0 H20: C, 63.76; H, 4.86; N, 6.76; Found: C. 63.82H, 4.72; N, 6.58. <br><br> Example 78 <br><br> 3-{4-[2-&lt;benzoxazol-2-yl-methyl-amino)-ethoxy]-ph«nyl}-2-[2-(3-methoxy-35 benzoyl)-phenylamino-propionic acid <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 110 <br><br> Using the protocol reported for Example 73, the title compound was synthesized from Intermediate 113 and 3-methoxybenzene boronic acid in 61% overall yield and isolated as a yellow solid: mp 76-80 "C; low resolution MS (ES*) m/e 566 (MH*); Anal. Calc. for C33H31N3061.5H20: C, 66.88; H, 5.78; N, 7.09; Found: C, 66.53H, 5 5.45; N. 6.78. <br><br> Example 79 <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(2-fnethoxy-benzoyl)-phenylamino-propionic acid <br><br> 10 Using the protocol reported for Example 73, the title was synthesized from Intermediate 113 and 2-methoxybenzene boronic acid in 49% overall yield and isolated as a yellow solid: mp 98-102 °C; low resolution MS (ES*) m/e 566 (MH*); Anal. Calc. for C^H^O^O H20: C, 65.88; H, 5.86; N, 6.98; Found: C. 65.98; H, 5.50; N, 6.64. <br><br> 15 <br><br> Simple go <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-«mino)-ethoxyl-phenyl}-2-[2-(3-mothyl-be izoyl)-ph»nylamino-propionic acid <br><br> Usir^ the pr**czji reported for Example 73, the title compound was synthesized 20 from Intermediate 113 and 3-methyibenzene boronic acid in 52% overall yield and isolated as a ye,low solid: mp 80-85 °C; low resolution MS (ES*) m/e 550 (MH*); Anal. Calc. for C33H31N3051.5H20: C, 68.74; H. 5.94; N, 7.29; Found: C. 68.49H, 5.66; N, 7.00. <br><br> 25 Example 81 <br><br> 2-[2-(4-dimethylaminomethyl-benzoyl)-phenylamino]-3-{4-[2-{5-fnethyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid hydrochloride <br><br> To a solution of Intermediate 123 (96 mg, 1.63 mmol), dimethylamine (0.85 mL, 0.17 mmol), and HOAc (3.7 mL, 0.065 mmol) in MeOH/THF ((3/1), 4 mL) was added 30 sodium cyanoborohydride (20 mg, 0.33 mmol). The resulting solution was stirred under N2 for 6h. The solution was diluted with EtOAc (50 mL) and washed with 1.0 M NaHC03 (20 mL) and brine (20 mL). This solution was dried over MgS04 and concentrated to a yellow semi-solid which was flash chromatographed on silica gel with EtOAc to elute the less polar products and then with EtOAc/MeOH 98/2 to elute 35 the product dimethylbenzylamine methyl ester: low resolution MS (ES) m/e 618 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 111 <br><br> (MH*); TLC (EtOAc); Rt 0.13. This material was hydrolyzed according to the procedure outlined in Example 32 to give the title compound (28.0 mg, 27% for 2 steps) as a yellow solid, mp 103-105 °C; low resolution MS (ES) m/e 604 (MH*); high resolution MS (FAB+) m/e (MH*) Calc. for C37H37N305: 604.2811, Found: 5 604.2816. <br><br> Example 82 <br><br> 2-[2-{4-aminpmathyl-benzoyl)-phenylamino]-3-(4-[2-{5-methyl-2-phenyl-oxazol-4-yl)-ethpxy]-phenyl}-propionic acid hydrochloride <br><br> 10 To a solution of Intermediate 123 (167 mg, 0.284 mmol) in THF (20 mL) was added sodium borohydride (11 mg, 284 mmol). The resulting solution was stirred under N2 for 30 min and quenched with acetone (1 mL). After stirring for an additional 30 min, the mixture was diluted with EtOAc (50 mL) and washed with 2.0 M NaOH, 1.0 M NaHC03 and brine (20 mL each). This solution W3S dried over MgS04 and 15 concentrated to a dark brown oil which was flash chromatographed on silica gel with EtOAc/hexane 2/3 as eluent to give the benzyl alcohol (129 mg, 77% yield) as a yellow oil: low resolution MS (ES*) m/e 591(MH*); TLC (EtOAc/hexane (1/1)); R( =0.33. To a solution of the above benzyl alconol (97 mg, 0.165 mrnol) and triethylamine (27.5 mL, 0.20 mmol) in CH2CI2 (3 mL) was added methanesulfonyl 20 chloride (14.0 mL, 0.18 mmol). The resulting solution was stirred under N2 for 3 h. The sc.Jtion was diluted with EtOAc (50 mL) and washed with 2.0 M HCI, water, 1.0 M NaHCOa and brine (20 mL each). The solution was dried over MgS04 and concentrated to give the corresponding mesylate (105 mg) as a yellow oil: low resolution MS (ES*) m/e 669 (MH*); TLC (EtOAc/toluene (1/3)); R, =0.74. To a 25 solution of the above mesylate (105 mg, 0.156 mmol) in DMF (2.5 mL) was added NaN3 (31 mg, 0.18 mmol). The resulting solution was stirred under N2 for 16 h. After adding 1.0 M NaHCOa (1 mL), the solvents were removed by rotary evaporation and the residue partitioned between water (20 mL) and EtOAc (50 mL). The EtOAc solution was washed with water and brine (20 mL each), dried over MgS04 and 30 concentrated to provide the benzyl azide (96.3 mg) as a yellow oil: low resolution MS (ES*) m/e 616 (MH*); TLC (EtOAc/hexane (1/2)); Rf =0.45. To a solution of the above azide (96 mg, 0.156 mmol) in THF (5 mL) and water (0.2 mL) was added triphenylphosphine (45 mg, 0.172 mmol). The resulting solution was stirred under N2 for 24 h. The solution was then diluted with EtOAc (50 mL) and washed with 2.0 M 35 NaOH (10 mL) and brine (25 mL). The organic solution was dried over MgS04 and <br><br> Printed trorn Mirnosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 112 <br><br> concentrated to a yellow oil which was flash chromatographed on silica gel with CHCI3/MeOH 95/5 as eluent to give the benzyl amine methyl ester (73 mg, 75% yield from the benzyl alcohol) as a yellow oil: low resolution MS (ES+) m/e 590 (MH*); TLC (CHCIj/MeOH (9/1)); R( =0.23. A solution of the above benzyl amine methyl ester in 5 THF/EtOH/I.O M LiOH (3/1/1, 5 mL) was stirred for 16 h under N2. The solvents were removed by rotary evaporation and the residue dissolved in water (15 mL) and washed with ether (25 mL). The aqueous layer was acidified to pH 2 with 2.0 M HCI to give a flocculent suspension. This mixture was concentrated to 5 mL and centrifuged (7100 rpm, 5 min). The aqueous solution was decanted and the 10 resulting yellow pellet resuspended in water (10 mL) and centrifuged as above (3X). The yellow solid thus obtained was suspended in water (2 mL) and lyophilized. The resulting yellow solid was suspended in EtOAc and centrifuged (3X). The resulting pellet was dried under vacuum to provide the title compound (56.8 mg, 82% yield) as a yellow powder: mp 134-136 DC; low resolution MS (ES*) m/e 576 (MH*); high 15 resolution MS (FAB*) m/e (MH*) Calc. for C35H33N3O5: 576.2498; Found: 576.2495; TLC (CHCIj/MeOH (4/1) +1 drop HOAc); Rf = 0.30. <br><br> Example 83 <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-«thoxy]-phenyl}-2-[2-(2,6-20 (Jimethylbenzoyl)-phenylamino-propionic acid <br><br> Using the protocol reported for Example 73, the title compound was synthesized from Intermediate 113 and 2,6-dimethylbenzene boronic acid in 13 % overall yield and isolated as a yellow solid: mp 85-90 °C; low resolution MS (ES*) m/e 564 (MH*); high resolution MS (FAB*) Calc. for CmH33N305(MH*): 564.2498; Found. 564.2484. <br><br> 25 <br><br> Example 84 <br><br> 3-(2-{1-carboxy-2-[4-&lt;2-{5-methyl-2-phenyl-oxaz0l-4-yl}-®thoxy)-pbenyl]-ethylamino&gt;-benzoyl benzoic acid <br><br> To a solution of Intermediate 124 (75 mg, 128 mmol) in acetone (5 mL) was added 30 dropwise 2.67 M Jones' reagent (48 mL, 128 mmol). The resulting dark green solution was stirred for 2 h. The reaction was quenched with the addition of iPrOH (1 mL). After stirring for an additional 15 min, the mixture was diluted with EtOAc (50 mL) and washed with 1.0 M HCI (20 mL), water (20 mL) and brine (10 mL). This solution was dried over MgS04 and concentrated to a brown oil which was flash 35 chromatographed on silica gel eluting with CHCI3/MeOH (98/2 containing 0.1% <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 113 <br><br> PCT/EP97/00916 <br><br> HOAc) to produce 3-(2-{1-carboxy-2-(4-(2-{5-methyl-2-pheriyl-oxazol-4-yl}-ethoxy)-phenyl]-ethylamino}-benzoyl benzoic acid methyl ester(25 mg, 33%) as a yellow oil: low resolution MS (ES) m/e 605 (MH*); TLC (CHCIa/MeOH (95/5)); R,= 0.20. The above methyl ester was hydrolyzed according to the procedure outlined in Example 5 32 to produce the title compound (24 mg, 98%) as a yellow solid: mp 107-110 °C; tow resolution MS (ES ) m/e 589 (M-H"); Anal. Calc. for C35H30N2070.5H20: C, 70.11; H, 5.21; N, 4.67; Found C. 69.99; H, 5.28; N, 4.51. <br><br> Example 85 <br><br> 10 2-[2-(3-hydroxymethyl-benzoyl)-phenylamino]-3-{4-[2-(5-fnQthyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl)-propionic acid <br><br> To a solution of Intermediate 124 (257 mg, 0.43 mmol) in THF (10mL) was added sodium borohydride (16.5 mg, 0.43 mmol). The resulting solution was stirred under N2 for 45 min and the quenched with acetone (1 mL) and stirred for an additional 10 15 min. After addition of 1.0 M NaHC03 (1 mL) the solvents were removed by rotary evaporation and the residue partitioned between EtOAc (50 mL) and water (20 mL). The EtOAc layer was washed with water (20 mL) and brine (10 mL) and dried over MgS04. This solution was concentrated to give a yellow oil which was flash chromatographed on silica gel (30 g) with EtOAc/hexane (2/3) to give the 2-[2-(3-20 hydroxymethyl-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)- <br><br> ethoxy]-phenyl}-propionic acid methyl ester (211 mg, 82%) as a yellow oil: low resolution MS (ES*) m/e 591 (MH*); TLC (EtOAc/hexane (1/1)); Rf= 0.39. A solution of the methyl ester (45 mg) was hydrolyzed according to the procedure outlined in Example 32 to produce the title compound (43 mg, 97%) as a yellow solid: mp 87-90 25 °C; low resolution MS (ES ) m/e 575 (M-H ); Anal. Calc. for C35H32N206. 0.5H20) C, 71.78; H, 5.68, N, 4.78; Found C, 71.70; H, 6.06; N. 4.45. <br><br> Example 86 <br><br> 2-[2-(3-aminomethyl-benzoyr)-phenyiamino]-3-{4-[2-{5-methyl-2-phenyl-oxazol-30 4-yl)-ethoxy]-phenyl}-propionic acid hydrochloride <br><br> Using the same synthetic route used for Example 82, Intermediate 124 was converted to the title compound: mp 138-140 °C; low resolution MS (ES*) m/e 576 (MH*); Anal. Calc. for C^H^^Og HCI 0.75H20) C, 67.19; H, 5.72; N, 6.72; Found C, 67.25; H, 5.92; N, 6.35. <br><br> 35 <br><br> PrinneJ froiri Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/009I6 <br><br> 114 <br><br> Example 87 <br><br> 2-{2-(3-dimethylaminomethyl-benzoyi)-phenylamir-oj-3-(4-[2-{5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic ac»d 'lydruchloride Using the analogous route used for Example 81. Intermediate 124 was converted to 5 the title compound: mp 120-124 °C; low resolution MS (ES+) m,e 604 (MH+); Anal. Calc. for C37H37N305 HCI 3H2C): C, 64.01; H. 6.39; N, 6.05; Found C, 63 62; H, 6.03; N, 5.78. <br><br> Example 88 <br><br> 10 2-{S)-(1-carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyf}- <br><br> ethylamino)-benzoic acid methyl ester <br><br> A solution of Intermediate 125 (582 mg, 1.13 mmol) in THF/EtOH/I.O M LiOH (3/1/1, 15 mL) was stirred under N2 for 2 h. A solution of 0.4M HCI (25 mL) was added and the mixture was then extracted with EtOAc (150 mL). This extract was washed with 15 brine (25 mL) and dried over Na2S04 and concentrated to a white solid. This material was flash chromatographed on silica gel with EtOAc (containing 0.1% HOAc) to produce the title compound (450 mg, 1: /o) as a white solid: mp 140-141 °C; 1H NMR (DMSO-d6, 400 MHz) 8 12.95 (brs. 1H). 7.94-7.88 (m, 3H). 7.77 (d, 1H, &gt;8.0), 7.49-7.45 (m, 3H), 7.35 (t, 1H, &gt;7.9), 7.08 (d, 2H, &gt; 8.5), 6.82 (d, 1H, 20 &gt;8.6), 6.69 (d, 1H, &gt;8.6), 6.59 (t, 1H, &gt; 7.5), 4.42-4.38 (m, 1H), 4.15 (t. 2H, &gt;6.7), 3.75 (s, 3H), 3.09 (dd. 1H, &gt;5.3,13.9), 2.96 (dd. 1H, &gt;6.1, 14.0), 2.89 (t, 2H, &gt;6.6), 2.32 (s, 3H); low resolution MS (ES+) m/e 501 (MH+); TLC (EtOAc): R,= 0.51; Chiral Chromatography (Chiralcel OD-H, 4.6 X 250 mm, EtOH/hexane (3/7) and 0.1% TFA, 0.7 mL/min): tr =7.8 min (major enantiomer), 7.2 min (minor 25 enantiomer): 88% ee; (a]D= -9.8°, a = -0.109°, c=1.11 (CH2CI2) (not corrected for ee); Anal. Calc. for C29H28N206. C, 69.51; H, 5.68; N, 5.54; Found: C, 69.40, H, 5.74; N, 5.42. <br><br> Example 89 <br><br> 30 2-(S)-(1 -carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethylamino)-benzoic acid 2-aminoethyl amide hydrochloride <br><br> To a solution of Iniermediate 126 (48.9 mg, 0.98 mmol), HOBt (5 mg, 37 mmol), triethylamine (20.4 mL, 146 mmol) and /erf-butyl A/-(2-aminoethyl)carbamate (16.9 mL, 107 mmol) in CH2CI2 (5 mL) was added 1-ethyi-3-(3-35 dimethylaminopropyl)carbodiimide (22.4 mg, 117 mmol). The resulting solution was <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 115 <br><br> stirred for 16 h under N2 and en diluted with EtOAc (50 mL) and washed with 25 mL each of 0.5 M HCI (2x), saturated NH4CI, water and 2.0 M NaHC03 (2X) and brine (10 mL). This solution was dried over MgS04 and concentrated to a brown oil which was flash chromatographed on silica gel with EtOAc/hexane 1/1 as eluent to 5 afford (37 mg, 59%) of a colorless oil: low resolution MS (ES*) m/e 643 (MH*); TLC (hexane/EtOAc (1/1)): Rr= 0.35. A solution of this material in THF/EtOH/I.O M LiOH (3/1/1, 5 mL) was stirred under N2 for 16 h. The solvents were removed by rotary evaporation and the residue taken up in water (10 mL) and acidified with 2.0 M HCI (2 mL). The resulting mixture was extracted with EtOAc (50 mL) Tnis extract was 10 washed with brine (10 mL), dried over MgS04 and concentrated to a colorless solid. This material was dissolved in 4.0 M HCI in dioxane (2 mL) and stirred under N2for 1 h. The dioxane was removed in vacuo to afford the title compound (42 mg, 100%) as a hygroscopic white solid: mp 110-115 °C; low resolution MS (ES*) m/e 529 (MH*); high resolution MS (FAB*) Calc. for C30H32N4O5 (MH*). 529.2451; Found. 15 529.2454; TLC (CHCI3/MeOH (9/1)): R,= 0.04. <br><br> Example 90 <br><br> 2-(S)-(1-carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}~ ethylamino)-benzoic acid 3-amlnopropyl amide hydrochloride <br><br> 20 By use of the analogous route to Example 89, the title compound was obtained in 95% yield from Intermediate 126 and ferf-butyl A/-(3-aminopropyl)carbamate as a hygroscopic white solid: mp 95-98 °C; low resolution MS (ES*) m/e 543 (MH*); high resolution MS (FAB*) Calc. for Ca^^^Og (MH*): 543.2607; Found: 543.2609; TLC (CHCI3/MeOH (9/1)): R,= 0.04. <br><br> 25 <br><br> Example 91 <br><br> 2-(5)-(1-carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-p^enyl}-ethylamino)-b«nzoic acid methyl amide <br><br> To a solution of Intermediate 126 (49.5 mg, 0.10 mmol), HOBt (6.7 mg, 49 mmol), 30 triethylamine (41.3 mL, 0.30 mmol) and methylamine (12.8 mL (40% solution in water). 0.15 mmol) in CH2CI2 was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (22.7 mg, 0.12 mmol). The resulting solution was stirred for 16 h under N2 and then diluted with EtOAc (50 mL) and washed with 20 mL each of 0.5 M HCI (2x), saturated NH4CI, water and 2.0 M NaHC03 (2x). This solution was dried over 35 MgS04 and concentrated to a yellow oil which was flash chromatographed on silica <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 116 <br><br> gel (10 g) with EtOAc/hexane (1/1) to afford 33.8 mg (67%) of a colorless oil: low resolution MS (ES*) m/e 514 (MH*); TLC (hexane/EtOAc (1/1)): Rf= 0.31. This material was hydolyzed according to the procedure outlined in Example 32 to afford the title compound (33.4 mg, 100%) as a white solid: mp 85-90 *C; H NMR (DMSO-5 dB, 400 MHz) 5 12.71 (s, 1H), 8.24-8.20 (m, 2H), 7.90-7.88 (m, 2H), 7.49-7X5 (m, 4H), 7.21 (t, 1H, &gt;7.2), 7.10 (d, 2H, &gt;8.5), 6.82 (d, 2H, &gt;8.6), 6.60-6.53 (.n, 2H), 4.23-4.22 (m, 1H), 4.15 (t, 2H, &gt;6.5), 3.02 (dd, 1H, &gt; 5.6,13.8), 2.92-2.87 (m, 3H), 2.69 (d, 3H, &gt;4.5), 2.33 (s, 3H); low resolution MS (ES*) m/e 500 (MH'); TLC (hexane/EtOAc (2/1)): Rf 0.06. <br><br> 10 <br><br> Example 92 <br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(3-hydroxy-benzoyl)-pheny lamino]-propionic acid <br><br> The title compound (140 mg) was prepared from 500 mg (0.88 mmol) of 15 Intermediate 130 and 111 mg (2.65 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via silica gel chromatography using MeOH/dichloromethane 1:19 as eluent: low resolution MS (ES) m/e 552 (MH*); RP-HPLC (50-100% CH3CN in water with 0.1% TFA buffer, 25 min): tr = 7.46 min. <br><br> 20 <br><br> faHtmpfr 93 <br><br> 3-{4-[2-{5-rnethyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-{2-(4-propylsulfamoyl-benzoyl)-phenylamino]-propionic acid <br><br> The title compound (31 mg) was prepared from 70 mg (0.102 mmol) of Intermediate 25 131 and 21 mg (0.31 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via trituration with MeOH/hexane (1:19) and .hen EtOAc/hexane (1:19): low resolution MS (ES) m/e 668.3 (MH*); RP-HPLC (50-100% CH3CN in water with 0.1% TFA buffer, 25 min): t, = 14.52 min; Anal. (Ca^NaOyS'O.SHjO) C, 65.66; H. 5.66; N. 6.21 Found C, 65.82; H, 5.61; N, 30 6.18. <br><br> Example 94 <br><br> 2-[2-(3-amino-benzoyl)-phenylamino]-3-{4-[2-{5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 117 <br><br> The title compound (35 mg) was prepared from 73 mg (0.13 mmol) of Intermediate <br><br> 132 and 19 mg (0.39 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via silica gel chromatography with ethyl MeOH/dichloromethane (gradient of 1:19 to 1:4) as eluent followed by <br><br> 5 trituration with MeOH/hexane (1:19) and then EtOAc/hexane (1:9): low resolution MS (ES) m/e 562 (MH*); RP-HPLC (0-100% CH3CN in water with 0.1% TFA buffer, 25 min): t, = 16.51 min; high resolution MS (FAB) m/e 562.2348 (MH*), C^Ha^Os requires 562.2342. <br><br> 10 Example 95 <br><br> 2-[2-(3-methari8sulfonylamino-benzoyl)-phenylamino]-3-{4-[2-(5-methyi-2-phenyl-©xazol-4-yl)-ethoxy]-phenyl}~propionic acid <br><br> The title compound (23 mg) was prepared from 60 mg (0.10 mmol) of Intermediate <br><br> 133 and 1 mg (0.28 mmol) of lithium hydroxide monohydrate according to the 15 method of Example 32 followed by purification via silica gel chromatography using <br><br> MeOH/dichloromethane (1:9 with 1% acetic acid) as eluent: low resolution MS (ES) m/e 640.2 (MH*); RP-HPLC (50-100% CH,CN in water with 0.1% TFA buffer. 25 min): t, = 12.02 min; high resolution MS (FAB) 640.2116 (MH*). C35Ha?N307S requires 640.2117. <br><br> 20 <br><br> Example 96 <br><br> 3-[2-(3-methoxycarbonylamino-benzoyl)-phenylamino]-3-(4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid <br><br> The title compound (28 mg) was prepared from 50 mg (0.79 mmol) of Intermediate 25 134 and 12 mg (0.28 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via silica gel chromatography with MeOH/dichloromethane (1:9 with 0.1% acetic acid) as eluent and trituration with EtOAc/hexane (1:9): low resolution MS (ES) m/e 642 (MNa*), 620 (MH*); RP-HPLC (50-100% CH3CN in water with 0.1% TFA buffer, 25 min): t, = 13.73 min); high 30 resolution MS (FAB) 620.2384 (MH*), Ca^^Oy requires 620.2397. <br><br> Example 97 <br><br> 2-[2-(3-hydroxy-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-pheiT,;-oxazol-4-y|)-ethoxy]-phenyl}-propionic acid <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 118 <br><br> The title compound (13 mg) was prepared from 50 mg (0.087 mmol) of Intermediate <br><br> 136 and 13.6 mg (0.32 mmol) of lithium hydroxide monohydrat? according to the method of Example 32 followed by purification via silica gel chromatography with MeOH/dichloromethane (gradient of 1:9 to 1:9 + 0.1% acetic acid) as eluent and <br><br> 5 trituration with MeOH/hexane (1:19): low resolution MS (ES) m/e 561 (M-H)*; RP-HPLC (50-100% CH3CN in water with 0.1% TFA buffer, 25 min): tr = 12.121 min; high resolution MS (FAB) m/e 563.2186 (MH*), C34H30N2O6 requires 563.2182. <br><br> Example 98 <br><br> 10 2-[2-{3-carbanoylmethPxy-b0nzoyl)-phenylamino]-3-{4-[2-{5-methyl-2-ph»nyl-oxazol-4-yl)*«thoxy]-ph«ny l}-propionic acid <br><br> The title compound (16 mg) was prepared from 73 mg (0.12 mmol) of Intermediate <br><br> 137 and 16.0 mg (0.38 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via silica gel chromatography with <br><br> 15 EtOAc/hexane (1:9) as eluent: low resolution MS (ES) m/e 618 (M-H)*; RP-HPLC (50-100% CHjCN in water with 0.1% TFA buffer, 25 rrin): tr = 10.06 min; high resolution MS (FAB) m/e 620.2384 (MH*), CMH33N307 requires 62G.2397. <br><br> Example 99 <br><br> 20 2(SH2-benzoyl-phenylamino)-3-{4-[2-(S-m«thyl-2-pyridin-4-ytaxa2ol-4-yl)-•thoxy]-ph*nyl)-propionic acid <br><br> The title compound (191 mg) was prepared from 210 mg (0.37 mmol) of Intermediate 143 and 49.0 mg (1.12 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via silica gel 25 chromatography with MeOH/dichloromethane (1:9) as eluent: low resolution MS (ES) m/e 548 (MH*); high resolution MS (El) m/e 548.2194 (MH*), 0,^2^,05 requires 548.2185. <br><br> Example 100 <br><br> 30 2(S)-(2-b«nzoyl-phenylamlno)-3-(4-{2-[5-m«»thyl-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid hydrochlpride <br><br> The title compound (429 mg) was prepared from 500 mg (0.84 mmol) of Example 42 and 110 mg (2.52 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via silica gel chromatography using 35 MeOH/EtOAc (gradient of 2:3 to 3:2 to 4:1) and acidified with 0.75 mL (0.74 mmol) <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 119 <br><br> PCT/EP97/00916 <br><br> of 1 M HCI in diethyl ether. The solvent was removed in vacuo to give the title compound as a hydrochloride salt: TLC (MeOH/EtOAc (2:3)): Rf = 0.17; low resolution MS (ES) m/e 585 (MH*); high resolution MS (El) m/e 585.2541 (MH*), C33H3BN4O4S requires 585.2536. <br><br> 5 <br><br> Example 101 <br><br> 2(S)-(2-benzoyl-phenylamlno)-3-(4-{2-I5-methyl-2-(4-tert-butoxycarbonyl-piperazin-1-yl)-thiazol-4-ylJ-ethoxy}-phenyl)-p/oplonic acid <br><br> The title rimpound (80 mg) was prepared from 140 mg (0.20 mmol) of Intermediate 10 147 and 26 mg (0.60 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via silica gel chromatography using MeOH/EtOAc (gradient of 3:7 to 1:1): low resolution MS (ES) m/e 669 (M-H)*; high resolution MS (FAB) m/e 671.2915 (MH*), C37H42N406S requires 671.2903. <br><br> 15 Example 102 <br><br> 2(S)-(2-b«nzoyl-phenylamino)-3-{4-{2-{5-methyl-2-pip«razln-1-yl-thlazoi-4-yl)-•thoxy)-ph«nyl}-prcp!cr.5e acid <br><br> To a stirred solution of 65 mg (0.10 mmol) of Example 101 in 1 mL of 1,4-dixoane was added 1.5 mL of 4 M HCI in 1,4-dtoxane. After stirring at RT for 3 h, the solvent 20 was removed in vacuo. The residue was purified by reverse phase HPLC using acetonitrile/water with 0.1% TFA buffer (gradient of 30-50% over 30 min) as eluent to give the title compound as a monotrifluoro acetate salt: low resoiut.on MS (ES) m/e 571.2 (MH*); high resolution MS (FAB) m/e 571.2382 (MH*), C32H34N404S requires 571.2379. <br><br> 25 <br><br> Example 103 <br><br> 2(S)-(2-bsnzoyl-phenylamino)-3-(4^2-[5-methyl-2-&lt;4-methylsulfonyl-piperazin-1-yl)-thiazol-4-yl]-ethoxy}-ph0nyl)-propionic acid <br><br> The title compound (123 mg) was prepared from 140 mg (0.21 mmol) of 30 Intermediate 149 and 26 mg (0.60 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via trituration with EtOAc/hexane (1:19): low resolution MS (ES) m/e 647 (M-H)*;high resolution MS (FAB) m/e 649.2151 (MH*). C33HMN406S2 requires 649.2155. <br><br> 35 Example 104 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 120 <br><br> 2(S)-(1-carboxy-2-{4-[2-(4-dimethylamino-phenyl)-ethoxy]-phenyl)-ethylamino)-banzoic acid mathyl astar <br><br> The title compound (30 mg) was prepared from 290 mg (0.61 mmol) of Intermediate 155 and 71 mg (1.83 mmol) of lithium hydroxide monohydrate according to the 5 method of Example 32 followed by purification via silica gel chromatography using MeOH/EtOAc (gradient of 0:^ to 1:9) as eluent: low resolution MS (ES) ni/e 461 (M-H)*; high resolution MS (FAB) m/e 463.2228 (MH*), C27HMN205 requires 463.2233. <br><br> Example 105 <br><br> 10 2(S)-[1-mathoxycarbonyl-2-(4-{2-{5-m#thyl-2-(4-m«thyl-pip«razin-1-yl)-thiazol-4-yl]-athoxy)-phanyl)-«thyiamino]-banzoic acid <br><br> The title compound (150 mg) was prepared from 360 mg (0.65 mmol) of Intermediate 156 and 92 mg (2.19 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via silica gel 15 chromatography using MeOH/EtOAc (gradient of 3:2 to 3:2 with 1% NH4GH to 4:1 with 1% NH4OH arid 1% water) as eluent: 1H NMR (DMSO-de, 400 MHz) 8 8.04 (d, 1H, J ■ 6.8), 7 72 (d, 1H. J = 8.0). 7.26 (t. 1H, J - 7.2), 7.04 (d, 2H, J ■ 8.4). 6.72 (d. 2H. J - 8.5), 6.59 (d, 1H, J « 8 7). 6 47 (t, 1H. J - 7.2), 4.06 (m. 3H). 3.74 (s, 3H), 3.26 (m, 4H), 3.03 (dd, 1H. 5.1. 13.8), 2.87 (dd, 1H. J' 6.5. 13.7), 2.79 (t. 2H. J 20 = 6.8), 2.34 (m. 4H), 2.19 (s. 3H). 2.17 (s, 3H); TLC (MeOH/EtOAc low resolution MS (ES) m/e 537 (M-H)*; high resolution MS (FAB) m/e 539.2328 (MH*), CjeH-^OsS requires 539.2328 <br><br> Exampl* nQ6 <br><br> 25 2(SH1 -carboxy-2-&lt;4-{2-(4-ch!oro-phenyl)-athoxy]-phenyl}-«thylamino)-banzoic acid mathyl eater <br><br> The title compound (142 mg) was prepared from 230 mg (0.49 mmol) of Intermediate 157 and 70 mg (1.67 mmol) of lithium hydroxide monohydrate according to the method of Example 32 followed by purification via silica gel 30 chromatography using MeOH/EtOAc (gradient of 0:1 to 1:19 to 1:9 with 1% NH4OH) as eluent: low resolution MS (ES) m/e 452 (MH)*; high resolution MS (FAB) m/e 454.1421 (MH*), C25H24N05CI requires 454.1421. <br><br> Example 107 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 121 <br><br> PCT/EP97/00916 <br><br> 2(S)-(1-carboxy-2-{4-I2-(4-trifluoromethoxy-phenyl)-ethoxy]-phonyl}-•thylamino)-benzoic acid methyl ester <br><br> The title compound (128 mg) was prepared from 280 mg (0.54 mmol) of Intermediate 159 and 72 mg (1.72 mmol) of lithium hydroxide monohydrate 5 according to the method of Example 32 followed by purification via silica ge) chromatography using MeOH/EtOAc (gradient of 0:1 to 1:19 with 1% NH4OH) as eluent. low resolutio- MS (ES) m/e 502 (MH)*; high resolution MS (FAB) m/e 504.1647 (MH*). C26H24NOBF3 requires 504.1634; TLC (MeOH/EtOAc (1:19)): Rf ■ 0.63. <br><br> 10 <br><br> Ewmp'f 199 <br><br> 3&lt;{4-(2-(Benzoxazol-2&gt;yl-methylamino)-ethoxy]-phanyl&gt;-3-(4-benzoyl* thienylamino)-propionic acid <br><br> A solution of 100 mg (0.18 mmol) of Intermediate 160 in 5 mL of ethanol and 1 mL of 15 water was heated to reflux with 30 mg of KOH for 45 minutes. The solution was concentrated to an oil, acidified with 0.1 N HCI to pH = 5. and extracted with chloroform (2 X 20 mL). Concentration and purification by silica gel chromatography eluting with EtOAc. then 1% acetic acid in EtOAc gave the title compound (45 mg) as a yellow solid: low resolution MS (ESP*) m/e 542 (MH*) ; TLC (EtOAc with 1% 20 AcOH): Rf - 0.38 <br><br> Eximplt 1Q» <br><br> 3-(4-[2-(Benzoxazol-2-yl-m«thylaminc)-ethoxy]-phenyl}-2-(2-&lt;4-bipheny Icarbony l)-phenylamino)-propionie acid. <br><br> 25 To a solution of 0.9 g (1.44 mmol) Intermediate 162 in 5 mL water and 50 mL MeOH was added 0.6 g (14.4 mmol) LiOH. The mixture was refluxed for 0.5 h, concentrated, and partitioned between pH 7 phosphate buffer solution and EtOAc. The concentrated organics were purified by silica gel chromatography eluting with 0-5% MeOH in CH2CI2 to yield the title compound as a yellow solid: 1H NMR (CDCI3, 30 200 MHz) s 9.00 (br s. 1H), 7.7-7.6 (m. 7H). 7.5-7.35 (m, 5H), 7.2-6.95 (m, 5H), 6.75 (m. 3H), 6.63 (t 1H. J = 7.5), 4.45 (br s, 1H), 3.27 (s, 3H). 3.2 (d, 2H, J = 5.7; Low resolution MS (CI) m/e 612 (MH+). <br><br> Example 110 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 122 <br><br> 3-(4-I2-(B«nzoxazol-2-yl-m»thyiamino)-ethoxy]-phenyl}-2-(2-{4-methoxy-benzoyl)-phenylamino)-propionic acid <br><br> The title compound was prepared from 0.29 g (0.5 mmol) Intermediate 164 and 31 mg LiOH (0.75 mmol) according to the procedure outlined in Example 32 followed by 5 purification via trituration with hexanes: H NMR (DMSO-d6, 200 MHz) 5 8.35 (d, 2H, J = 7.3), 7.55 (d, 2H, J - 8.6), 7.39-7.25 (m, 5H). 7.15-6.9 (m, 5H). 6.8 (m, 3H), 6.6 (m. 1H), 4.3 (m. 1H), 4.15 (m, 2H), 3.8 (m, 5H), 3.2 (s. 3H). 3.0 (m, 2H); Low resolution MS (CI) m/e 566 (MH*). <br><br> 10 Example 111 <br><br> 3-(4-[2-&lt;Benzoxazol-2-yl-methylamlno)-ethoxy]-ph0nyl}-2-(2-(4-mathyl-beruoyl)-phenylamino)-prcpionic acid <br><br> To a solution of 760 mg (1.35 mmol) of Intermediate 165 in 70 mL MoOH and 15 mL water was added 0.57 g (13.5 mmo') LiOH. The stirred solution was refluxed for 4 h. 15 concentrated, taken up into water (15 mL) and CHCI3 (15 mL) and the aqueous phase adjusted to pH * 6-7 with 1.0 N HCI. Extraction with CHCI3 followed by silica gel chromatography purification eluting first with EtOAc, then EtOAc with 0.5% AcOH provided 90 mg of the title compound: TLC (EtOAc with 0.5% AcOH). R, * 0 44 ; Low resolution MS (ESP*) m/e 550 (MH*). <br><br> 20 <br><br> Example 112 <br><br> 3-{4-[2*(Benzoxazol-2-yl-methylamino)-ethoxy]-phenyl)-2-(2-(2 -methyl-b«nzoyl)-phenylamino)-propionic acid <br><br> The title compound was prepared from Intermediate 166 (687 mg, 1.22 mmol) as 25 described for the preparation of Example 111 to yield 500 mg of crude product. Purification by silica gei chromatography eluting first with 40-50% EtOAc in hexanes followed by 10% MeOH in CH2CI2 gave 200 mg of the title compound. A pure fraction (21 mg) was obtained by preparative TLC (2000 microns, elution with EtOAc containing 0.5% AcOH): TLC (MeOH/CH2CI2, 1/9): R( = 0.35; Low resolution MS (CI) 30 m/e 550 (MH*). <br><br> General Procedure for Preparation of Examples 113-128 <br><br> A Whatman syringeless filter device PTFE "Autovial" 12mL capacity with a 0.45 mm PTFE membrane with glass microfiber was charged with 100mg (1.1 mmol) of 35 Intermediate 118, followed by 4mL of THF, the appropriate alcohol (5 mmol). DEAD <br><br> Prin'ed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 123 <br><br> (5 mmol),and either Ph3P orTBP (5 mmol). Alternate conditions used TMAD (1,1*-azobis(N,N-dimethylformamide) (5 mmol) and 1:1 CH2CI2:THF as a solvent. After rotating the autovials on an orbit shaker for ~1.5h the resin was treated with a series of solvent washes of the resin in the following order. THF,Me0H,THF,DMF,CH2CI2, 5 then dried for 30min. The resin was cleaved by treatment with 10% trifluoroacetic acid in CH2CI2 for Ihr.The filtrates were collected under vacuum in a Baker spe-24G Glass Column Processor unit, evaporated under N2, and dned under high vacuum for 24h affording crude product. Compounds were then subjected to further purification by HPLC Cia Waters Delta Prep 3000,Column: YMC-Pack ODS 10 AA12S05-2520WT 250X20 mm I.D.S-5mm,120A, 0-100% B over 1/2h, flow 18mL/min, monitored at 220, B=0.1% trifluoroacetic acid in acetonitriie, A=0.1% trifluoroacetic; acid in water. Analytical Column: YMC-Pack ODS AA1 2S05-2520WT 250X4.6 mm I D. S-5mm,120A, 0-100% B at 1.5mL/min. over 30 min, monitored at 220,B*0 1% trifluoroacetic acid in acetonitriie, A=0.1% trifluoroacetic acid in water. <br><br> 15 <br><br> Eximplf 113 <br><br> 2-(2-Benzcyl-pheny(amino)-3-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-propionic acid <br><br> Reaction of Intermediate 118 with 2-(4-chtorophenyl) ethanol using the general 20 procedure described above afforded a yellow solid: MS (ESP+) m/e 538 (MH ); Anal. (C30H26NO4CI'TFA); HPLC: t, = 22.43 min. <br><br> Example 114 <br><br> 2-(2-B*nzoyl-phcnylamiirio)-3-{4-[2 {4-methyl-thiazol*5-yl)&lt;ethoxy)-phc; 25 propionic acid <br><br> Reaction of Intermediate 118 with 2-(4-methyMhiazol-5-/l) ethanol using th- ger.p.al procedure described above afforded a yellow solid: MS (ESP+) m/e 4G7 MH*); Anal. (C28H26N204S «TFA); HPLC: tr =17:43 min. <br><br> 30 Example 115 <br><br> 2-(2-Benzoyl-phenylamino)~3~(4-2[-(4-chloro-phenyisulfanyl)ethoxy]- phenyl-propionic acid <br><br> Reaction of Intermediate 118 with 2-(4-chlorophenylsutfanyl) ethanol using the general procedure described above afforded a yellow solid: MS (ESP+) m/e 532 35 (MH*); Anal. (C30H26CINO4S*TFA); HPLC: tr =22.65 min. <br><br> Printed from Mimosa <br><br> WO 97/31907 PCT/EP97/00916 <br><br> 124 <br><br> Example 116 <br><br> 2-(2-Benzoyl-phonylamino)-3-[4-(4-i*opropyl-benzyloxy)-phenyl}-propionic acid Reaction of Intermediate 118 with 4-isopropyl benzyl alcohol using the general 5 procedure described above afforded a yellow solid: MS (ESP+) m/e 516 (M+Na ), 494 (MH ); Anal. (CjjH^NCVTFA); HPLC. t, =23.36 min. <br><br> 2-{2-B«nzoyl-ph*nylamino)-3-{4-&lt;4-chloro-b»nzyloxy)-phenyl]-propionic acid 10 Reaction of Intermediate 118 with 4-chlorobenzyl alcohol using the general procedure described above afforded a yellow solid: MS (ESP+) m/e 486 (MH ); Anal. (C29Hj4CIN04'TFA); HPLC. i, =21.95 min. <br><br> Example 118 <br><br> 15 2-&lt;2-Benzoyl-ph«nylamino)-3-{4-[3-&lt;4-methoxy-phenyl)-propoxy]-phanyl}-propionic acid <br><br> Reaction of Intermediate 116 with 3-(4-methoxyphenyl) propanol using the general procedure described above afforded a yellow solid: MS(ESP+)m/e 510 (MH ); Anal.(C32H31N06«TFA); HPLC: tr »23 48 min <br><br> 20 <br><br> pMmplf 119 <br><br> 2-(2-Benzoyl-phenylamlno)-3-{4-{2-(4-dlmethylamlno-phenyl)-ethoxyJ-phenyl}-proplonlc acid <br><br> Reaction of Intermediate 118 with 2-(4-N,N-dimethylaminophenyl) ethanol using the 25 general procedure described above afforded a yellow solid: MS(ESP+) m/e 509 (MH*); Anal.(CMHMN204«TFA); HPLC: tr *16.81 min <br><br> Example 120 <br><br> 2-&lt;2-Benzoyl-phenylamino)-3-{4-[2-(4-bromo-phenoxy)-ethoxy]-phenyl}-30 propionic acid <br><br> Reaction of Intermediate 118 with 2-(4-bromophenoxy) ethanol using the general procedure described above afforded a yellow solid. MS (ESP-*-) m/e 560 (MH ); Anal. (CjoH^BrNOs'TFA); HPLC: tr =21.28 min. <br><br> 35 Example 121 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/!EP97/00916 <br><br> 125 <br><br> 2-{2-Benzoyl-phenylamino)-3-{4-[2-&lt;5-nitro-pyridin-2-yloxy)-ethoxy]-phenyl}-propionic acid <br><br> Reaction of tntermediate 118 with 2-{5-nitropyridin-2-yloxy) ethanol using the general procedure described above afforded a yellow solid: MS(ESP+) m/e !&gt;28 (MH ); 5 Anal.(CMH25N3CVTFA); HPLC: t, =20.02 min. <br><br> Example 122 <br><br> 2-(2-Benzoyl-phenylamino)-3-(-4-{2-{3-&lt;6-methyl-pyridin-2-yl)-propoxyJ-ethoxyl}-phenyl)-propionic acid 10 Reaction of Intermediate 118 with 2-[3-(6-methylpyridin-2-yl) propoxy] ethanol using the general procedure described above afforded a yellow solid: MS(ESP+) m/e 539 (MH*); Anal^CjjH^NjOs'TFA); HPLC: tf =16.35 min. <br><br> Example 123 <br><br> 15 2-(2-Benzoyl-pheny lamino)-3-[4-42-pyridin-3-yl-«thoxy]-phenyl]-propionii; acid Reaction of Intermediate 118 with 2-(2-pyridinyl) ethanol using the general procedure described above afforded a yellow solid: MS(ESP+) m/o 467 (MH ); Anal.(C29H2flN204,TFA); HPLC: t, -15.84 min. <br><br> 20 Example 124 <br><br> 2-(2-Benzoyl-pheny!amir&lt;o)-3-{4-[2-(3-m«thyl-6-oxo-6H-pyridizin-1-yl)-«thoxy]-phenyl)-propionic acid <br><br> Reaction of Intermediate 118 with 2-(3-meihyl-6-oxo-6H-pyridazin-1-yl) ethanol using the general procedure described above afforded a yellow solid: MS(ESP+) m/e 498 25 (MH*); Anal.(C29H27N306*TFA); HPLC: tr =18 64 min. <br><br> Exwmplt 125 <br><br> 2-(2-Ben*oyl-ph*nylamino)-3-{4-[2-(4-trlfluororn«thoxy-ph«nyl)- ethoxy]- <br><br> phenyl)-propionic acid <br><br> 30 Reaction of Intermediate 118 with 2-(4-trifluoromethoxyphenyl) ethanol using the general procedure described above afforded a yellow solid: MS(ESP+) m/e 5t0 (MH*); Anal.tCa^NOsFa'TFA). <br><br> Exwpplt 126 <br><br> Printed from Mimosa <br><br> WO 97/31907 PCT/EP97/00916 <br><br> 126 <br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(3-cyano-phanoxy)-ethoxy]-phenyl}-propionic acid <br><br> Reaction of Intermediate 118 with 2-(3-cyanophenoxy) ethanol using the general procedure described above afforded a yellow solid. MS(ESP+) m/e 507 (MH ); 5 Anal.(C31H26N205-TFA). <br><br> Example 127 <br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(6-methoxy-pyridin-2-ylsulfanyl)-ethoxy)-phenyl}-proplonic acid 10 Reaction of Intermediate 118 with 2-(6-methoxy-pyridin-2-ylsulfanyl) ethanol using the general procedure described above afforded a yellow solid; MS(ESP+) m/e 534 (MH*); Anal (C3oH2eN205S*TFA); HPLC: t, =21.88 min. <br><br> Eximplt 129 <br><br> 15 2-{2-B*nzoyl-phanylamino)-3-{4-[1-(4-nltroph«nyl)-pyrrolidin-2-ylmethoxy]-phenyl}-propionic acid <br><br> Reaction of Intermediate 118 with (S)-(-)-1-(4-nitrophenyl)-2-pyrrolidineMeOH using the general procedure described above afforded a yellow solid: MS(ESP+), m/e 566 (MH*); Anal (C„H31N306-TFA), HPLC: tr =22 07 min <br><br> 20 <br><br> Alternative Intermediate 23 <br><br> Intermediate 23 was prepared using the following alternative process. L-Tyrosine methyl ester (1.00 equiv., 0.96 wt ), 2-benzoyl-cyclohexanone (W.A. Denny et al., J.Med.Chem., 21(5), pp430-437 (1978)) (1.00 equiv., 1.00 wt.) and 25 dimethoxyethane (5 volumes), were combined and heated to reflux overnight. 2-2.5 volumes of solvent were removed by distillation, and the suspension was allowed to cool to ambient temperature. The product was collected by vacuum filtration, <br><br> washed with 0.5 volumes of cok) dimethoxyethane and dried under house vacuum overnight. This product (1.00 wt., 1.00 equiv.) was combined with 10% palladium on 30 carbon, (0.10 wt), para-nitrotoluene (0.75 equiv., 0.27 wt ), and 1-butanol (8.0 • 12.0 volumes) and heated to vigorous reflux for four to eighteen hours under a nitrogen atmosphere. The suspension was filtered hot, under nitrogen, through a celite plug, the pad was washed with hot 1-butanol (2-5 volumes) and the filtrate cooled to <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 127 <br><br> ambient temperature. After cooling, the crystals were collected by vacuum filtration, washed once with cold absolute ethanol, and air dried. <br><br> Alternative Intermediate 117 <br><br> 5 Intermediate 117, the acid analog of the methyl ester Intermediate 23, was prepared by the following alternative process. To a suspension of Intermediate 23 (1.00 equiv., 1.0 wt) in tetrahydrofuran (1.2 - 2.5 vol) at 15-25°C was added a solution of sodium hydroxide (2.2 equiv., 0.24 wt) in water (1.2-1.4 vol.) at a rate to keep the temperature less then 25*C. After addition was complete, the solution was warmed 10 to 15-25"C and stirred until no starting material remains by TLC. 2-3 M Hydrochloric Acid (2.2 - 2.6 equiv., 2.7-3.3 vol.) was added until a pH of &lt;3 was reached, keeping the temperature below 25*C. Ethyl Acetate (6.0-7.0 vol.) was added, the mixture was vigorously stirred for 0.3 • 1.0 hour, then the layers separated and the aqueous layer discarded. The organic layer was extracted with b. ne (2.0 -3.0 vol.) and the 15 brine discarded. The organic layer was concentrated :. 1 5-2.5 volumes and alioweu To crystallize. Heptane (4.0 - 5.0 vol.) was adtirJ to complete the crystallizntion. The crystals were collected by filtration washed with heptane (4.0 -5.0 vol.) an^ dried. <br><br> 20 Intormtdittf Iff? <br><br> The mesylate analog of the oxazole alcohol from Maybridge. was prepared using the following process. To a suspension of 2-(&amp;-methyi-2-phenyk&gt;xazol-4-yl)ethanoll (commercially available from Maybridge), (1.0 eq, 1.0 wt) in toluene (10 vol) and triethylamine (1.1 eq, 0.75 vol) at 20 - 25 °C was added methanesulfonyl chloride 25 (1.1 eq, 0.42 vol) at a rate which allowed the temperature to rise to 40 *C. After the addition was complete the reaction was allowed to cool to 20 - 25 °C over 1 h. The organic phase was washed with water (3.5 vol) and brine (1.2 vol). The resulting solution was concentrated to 5 volumes, and stirred at 25 °C until crystallization commenced. Heptane (5 vol) was added to complete crystallization, and the mixture <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 128 <br><br> was stirred at 25"C for 1 h. The solids were collected by filtration, washed with heptane (4.0 vol) and dried in a vacuum oven at 50 °C. <br><br> Alternative Example 29 <br><br> 5 The compound of Example 29 was prepared by the following alternative method. To a slurry of the phenol, Intermediate 117, (1.0 eq, 1.0 wt), in dimethylsulfoxide (1.0 vol)/water (2.0 vol) was added solid NaOH (2.4 eq, 0.26 wt). The resulting solution was stirred at 50 "C and a solution of the mesylate, Intermediate 167 (1.28 eq, 1.0 wt), in dimethylsulfoxide (3.0 vol) was added dropwise at a rate to maintain a 10 temperature of 48 - 52 *C. This mixture was stirred at 48 - 52 *C for 22 hours, <br><br> cooled to 25 *C, and washed three times with methyl tert-butyl ether (6.0 vol). The aqueous phase was diluted first with elhanol (2.0 vol), followed by glacial acetic acid (2.0 vol), and then water (6.0 vol) was added dropwise to the aolution with vigorous stirring. Seed crystals were added when the solution became turbid and cloudy. 15 The resulting precipitate was filtered, washed with water (6.0 vol), then ethanol:water/50:50 (12.0 vol) and vacuum dried at 50 °C. The resulting yellow solid was recrystallized from ethanol:water/95:5 (18.0 vol), and vacuum dried to constant weight at 50 *C. <br><br> 20 s+cood Ait? roatjvt Emmpl* 29 <br><br> The compound of Example 29 was prepared by the following second alternative method. To a mixture of phenol ester, Intermediate 23, (1 wt) 2-(5-methyl-2-phenyloxazol-4-yl)ethanol. (commercially available from Maybridge) (0.65 wt), and triphenylphosphine (0.88 wt) in toluene (3.5 vol) at 4C" was added a solution of 25 diisopropyl azodicarboxylate (0.66 vol) in toluene (0.5 vol) dropwise at such a rate to keep the tamperature between 40 and 50 °C. After the reaction was complete (HPLC) the resulting solution was concentrated under vacuum at 50°C by removing toluene (2 vol), allowed to cool to room temperature, diluted with methyl tert-buty) ether (4 vol) and chilled to 0 °C. After 1 hour at 0 °C the mixture was filtered to <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> 129 <br><br> PCT/EP97/00916 <br><br> remove triphenylphosphine oxide and the filter pad was washed with cold (0 °C) methyl tert-butyl ether (2 vol). The resulting solution was washed with 2.5N NaOH (2.5 vol, 0 °C). 2.5 N NaOH (2.5 vol) was added and the mixture was stirred at room temperature until hydrolysis was complete (HPLC). Dimethyl sulfoxide (5 vol) was 5 added and the phases separated. The aqueous phase was washed with methyl tert-butyl ether (3 vol), diluted first with ethanol (2.0 vol), followed by glacial acetic acid (2.0 vol), and then water (6.0 vol) was added dropwise to the solution with vigorous stirring. Seed crystals were added when the solution became turbid and cloudy. The resulting precipitate was filtered, then washed with ethanol:water/50.50 (6 vol). <br><br> 10 The resulting solids were slurried with hot ethanol:water/50:50 (6 vol) and filtered at 70°C. The resulting yellow solid was recrystallized from ethanol:water/95:5 (13.0 vol), and vacuum dried to constant weight at 50 °C. <br><br> 15 <br><br> DEMONSTRATION OF EFFICACY OF COMPOUNDS <br><br> PROTOCOLS <br><br> 1 PPARgamma Transient Cotransfection Assay: The pSG5-mPPARg and pSG5-hPPARg chimeric receptor expression plasmids and the (UAS)9-tk-CAT reporter plasmid have been previously described (Kliewer, SA, et. al. Cell 83, 813-819 20 (1995); J. M. Lehmann et. al., J. Biol. Chem. 12953-12956, 270 (1995)). Transient cotransfection assays using these plasmids were performed as previously described (Kliewer, S. A., et. al. Cell 83, 813-819 (1995); J. M. Lehmann ei. al., J. Biol. Chem. 12953-12956, 270 (1995)) <br><br> 25 2. hPPARgamma Ligand Binding Assay: The PPAR-gamma ligand binding domain (amino acids 195-475) was expressed with an N-terminal 10x-histidine tag in E. coli cells. The cells were lysed and receptor was purified by means of the epitope tag. The stock solution of protein was diluted to 200 nM in assay buffer (50mM Tris, 50mM KCI, pH 8 20mM CHAPS, 2mM EDTA 10mM DTT (Fresh)) just before use. 30 Test compounds were prepared as 6mM stock solutions in DMSO. Two sequential 10-fold dilutions were made into assay buffer to give compound and DMSO concentrations of 60 uM and 1%, respectively.12.5 uL of the diluted compound was added to a well in the left-most column of a microtiter plate <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 130 <br><br> containing 67.5 uL of assay buffer, the contents of the well were mixed, and 25 uL of this solution was transferred to the next well where it was mixed with 50 uL of assay buffer (3-fold dilution). This process was repeated to give a total of eleven (11) concentrations arrayed row-wise in the 96 well plate for each test compound. The 5 right-most column of wells was used for controls. For each experiment, an appropriate amount of 3H-BRL 49,653 was blown to dryness in a glass vial, resuspended in assay buffer (50mM Tris, 50mM KCI, pH 8 20mM CHAPS, 2mM EDTA 10mM DTT (Fresh)) to give a 400 nM concentration, vortexed, and sonicated for 10 seconds. Radioligand ([3H]-BRL 49,653) and receptor was added to each 10 well of the plate containing test compound. Plates were incubated at room temperature for 2hrs, and then cooled on ice for 30 minutes. 50 uL samples from each well of a single test plate were simultaneously loaded onto an equilibrated AGTC 96 well gel filtration block (Advanced Genetics Technology Corp.) using a Zymak Rapidplate automated pipettor. The block was placed on top of a dean 15 microtiter plate and centrifuged @1,100 X g for 4 min. 200 uL of scintillation fluid was added to each well, the plates were sealed and allowed to equilibrate for at least 4 hours before counting in a Wallac 1250 Microbeta counter. <br><br> Nonspecific binding as assessed by control wells containing an excess of [3H]-BRL 49,653 was subtracted from all wells and plots of compound concentration 20 versus CPM bound were constructed. Ki's were determined from a nonlinear least squares fit of the data to a simple competitive binding model. For the purposes of data analysis, a Kd for [3H]-BRL 49,653 of 200 nM was utilized. <br><br> 3. in vivo Evaluation: Experiments were performed on db/db mice (n=40-48), 25 approximately 60 day old, divided into either vehicle or treatment groups. From each group 8-12 animals were placed in Nalgene metabolic cages, 2 per cage. The remaining animals are housed in standard rack cages; 3-4 per cage. Test compounds were dissolved in an appropriate vehicle. Animals were administered either the vehicle or the compound (dose = 5 mg/kg) delivered at 5 ml/kg, b i d., via 30 oral gavage for fourteen days. Daily measurements were made of mice housed in metabolic cages to determine consumption of food and water, urine output and urinary glucose excretion and changes in body weight. Animals housed in rack cages were weighed approximately every four days to monitor changes in body weight. An equal number of animals from each group were sampled on days 0, 4, 7 35 and 14. Mice were anesthetized with isolflurane, blood samples were obtained by <br><br> Printed trom Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 131 <br><br> cardiac puncture and analyzed to determine plasma levels of glucose, insulin, total cholesterol, triglycerides and non-esteiified free fatty acids (NEFA's). <br><br> BIOLOGICAL DATA FOR EXAMPLES 1-128 <br><br> PPARg PPARg <br><br> PPARg <br><br> Example Number <br><br> Fold. Act. <br><br> ECw (nM) <br><br> Ki (nM) <br><br> Example 1 <br><br> 26 <br><br> 80 <br><br> 55 <br><br> Example 2 <br><br> 23 <br><br> 100 <br><br> 1000 <br><br> Example 3 <br><br> 3 <br><br> Example 4 <br><br> 20 <br><br> 3000 <br><br> 1000 <br><br> Example 5 <br><br> 10 <br><br> 9000 <br><br> &gt;3000 <br><br> Example 6 <br><br> 4 <br><br> Example 7 <br><br> 5 <br><br> Example 8 <br><br> 720 <br><br> 21 <br><br> Example 9 <br><br> 630 <br><br> 700 <br><br> Example 10 <br><br> 170 <br><br> 300 <br><br> Example 11 <br><br> 23 <br><br> 10 <br><br> 110 <br><br> Example 12 <br><br> 5 <br><br> 20 <br><br> Example 13 <br><br> 60 <br><br> 1300 <br><br> Example 14 <br><br> 18 <br><br> 1 <br><br> 80 <br><br> Example 15 <br><br> 1 <br><br> 40 <br><br> Example 16 <br><br> 1 <br><br> 20 <br><br> Example 17 <br><br> 1 <br><br> 80 <br><br> Example 18 <br><br> 5 <br><br> 10 <br><br> Example 19 <br><br> 65 <br><br> 185 <br><br> Example 20 <br><br> 120 <br><br> 180 <br><br> Example 21 <br><br> 150 <br><br> 530 <br><br> Example 22 <br><br> 20 <br><br> 65 <br><br> Example 23 <br><br> 1 <br><br> 50 <br><br> Example 24 <br><br> 1 <br><br> 30 <br><br> Example 25 <br><br> 1 <br><br> 70 <br><br> Example 26 <br><br> 670 <br><br> 1900 <br><br> Example 27 <br><br> 400 <br><br> 300 <br><br> Example 28 <br><br> 25 <br><br> Example 29 <br><br> 0.2 <br><br> 20 <br><br> Example 30 <br><br> 50 <br><br> 300 <br><br> Example 31 <br><br> 450 <br><br> 145 <br><br> Example 32 <br><br> 1 <br><br> 25 <br><br> Example 33 <br><br> 0.1 <br><br> 30 <br><br> Example 34 <br><br> 0.5 <br><br> 10 <br><br> % lowering of plasma glucose <br><br> 58% <br><br> 63% <br><br> 70% <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> Example 35 Example 36 Example 37 Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 Example 44 Example 45 Example 46 Example 47 Example 48 Example 49 Example 50 Example 51 Example 52 Example 53 Example 54 Example 55 Example 56 Example 57 Example 58 Example 59 Example 60 Example 61 Example 62 Example 63 Example 64 Example 65 Example 66 Example 67 Example 68 Example 69 Example 70 Example 71 Example 72 Example 73 Example 74 Example 75 Example 76 Example 77 Example 78 <br><br> 132 <br><br> 5 <br><br> 1 <br><br> 40 <br><br> 380 <br><br> 1 <br><br> 50 <br><br> 1 <br><br> 160 <br><br> 865 <br><br> 3000 <br><br> 5 <br><br> 70 <br><br> 5 <br><br> 70 <br><br> 5 <br><br> 1000 <br><br> 1000 <br><br> 185 <br><br> 15 <br><br> 1 <br><br> 30 <br><br> 900 <br><br> 750 <br><br> 50 <br><br> 240 <br><br> 20 <br><br> 115 <br><br> 10 <br><br> 80 <br><br> 50 <br><br> 390 <br><br> 350 <br><br> 140 <br><br> 80 <br><br> 100 <br><br> 25 <br><br> 70 <br><br> 250 <br><br> 3000 <br><br> 460 <br><br> 1400 <br><br> 1 <br><br> 10 <br><br> 150 <br><br> 1245 <br><br> 1 <br><br> 30 <br><br> 95 <br><br> 100 <br><br> 1 <br><br> 15 <br><br> 15 <br><br> 10 <br><br> 20 <br><br> 20 <br><br> 20 <br><br> 30 <br><br> 10 <br><br> 50 <br><br> 140 <br><br> 40 <br><br> 230 <br><br> 20 <br><br> 0.2 <br><br> 10 <br><br> 1 <br><br> 10 <br><br> 100 <br><br> 290 <br><br> 200 <br><br> 250 <br><br> 150 <br><br> 5 <br><br> 30 <br><br> 25 <br><br> 115 <br><br> 55 <br><br> 800 <br><br> 100 <br><br> 75 <br><br> 10 <br><br> 110 <br><br> 65 <br><br> 155 <br><br> 200 <br><br> 40 <br><br> Printed from Mimosa <br><br> WO 97/31907 <br><br> PCT/EP97/00916 <br><br> 133 <br><br> Example 79 <br><br> 30 <br><br> 50 <br><br> Example 80 <br><br> 10 <br><br> 10 <br><br> Example 81 <br><br> 400 <br><br> 130 <br><br> Example 82 <br><br> 25 <br><br> 65 <br><br> Example 83 <br><br> 165 <br><br> 350 <br><br> Example 84 <br><br> 55 <br><br> Example 85 <br><br> 20 <br><br> Example 86 <br><br> 30 <br><br> 650 <br><br> Example 87 <br><br> 465 <br><br> 1160 <br><br> Example 88 <br><br> 0.5 <br><br> 50 <br><br> Example 89 <br><br> 60 <br><br> 3000 <br><br> Example 90 <br><br> 3000 <br><br> Example 91 <br><br> 20 <br><br> Example 92 <br><br> 400 <br><br> 20 <br><br> Example 93 <br><br> 55 <br><br> 100 <br><br> Example 94 <br><br> 10 <br><br> 40 <br><br> Example 95 <br><br> 700 <br><br> 380 <br><br> Example 96 <br><br> 300 <br><br> 280 <br><br> Example 97 <br><br> 20 <br><br> 5 <br><br> Example 98 <br><br> 375 <br><br> 10 <br><br> Example 99 <br><br> 1 <br><br> 70 <br><br> Example 100 <br><br> 1 <br><br> 40 <br><br> Example 101 <br><br> 1 <br><br> 70 <br><br> Example 102 <br><br> 80 <br><br> 20 <br><br> Example 103 <br><br> 180 <br><br> Example 104 <br><br> 900 <br><br> 3000 <br><br> Example 105 <br><br> 35 <br><br> 140 <br><br> Example 106 <br><br> 300 <br><br> 140 <br><br> Example 107 <br><br> 190 <br><br> 40 <br><br> Example 108 <br><br> 20 <br><br> 80 <br><br> Example 109 <br><br> 200 <br><br> 700 <br><br> Example 110 <br><br> 65 <br><br> 50 <br><br> Example 111 <br><br> 10 <br><br> 70 <br><br> Example 112 <br><br> 10 <br><br> 130 <br><br> Example 113 <br><br> 80 <br><br> 150 <br><br> Example 114 <br><br> 250 <br><br> 140 <br><br> Example 115 <br><br> 165 <br><br> 200 <br><br> Example 116 <br><br> 165 <br><br> 470 <br><br> Example 117 <br><br> 1000 <br><br> 655 <br><br> Example 118 <br><br> 500 <br><br> 730 <br><br> Example 119 <br><br> 470 <br><br> 3000 <br><br> Example 120 <br><br> 350 <br><br> 65 <br><br> Example 121 <br><br> 320 <br><br> 100 <br><br> Example 122 <br><br> 500 <br><br> 625 <br><br> Printed from Mimosa <br><br></p> </div>

Claims (36)

  1. <div class="application article clearfix printTableText" id="claims"> <p lang="en"> WO 97/31907<br><br> PCT/EP97/00916<br><br> 134<br><br> Example 123 620 280<br><br> Example 124 810 130<br><br> Example 125 200 160<br><br> Example 126 800 370<br><br> Example 127 460 160<br><br> Example 128 20 70<br><br> Printed from Mimosa<br><br> WO 97/31907<br><br> 135<br><br> PCT/EP97/00916<br><br> What is claimed is:<br><br>
    1. A compound having the formula (I):<br><br> V-(|)<br><br> COjR1<br><br> \|—Alk-~&lt;<br><br> A- B— O<br><br> wherein<br><br> A is selected from the group consisting of .<br><br> 10<br><br> (i) phenyl, wherein said phenyl is optionally substituted by one or more halogen atoms, Chalky!, C,.3alkoxy, C,.3 fluoroalkoxy, nitrile, or -NR7R8 where R7 and R® are independently hydrogen or Chalky I;<br><br> 15 (ii) a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and<br><br> (iii) a fused bicyclic ring c wherein ring C represents a heterocyclic group as defined in point (ii) above, which bicyclic ring is attached to group B 20 via a ring atom of ring C;<br><br> B is selected from the group consisting of.<br><br> (iv) C, 6 alkylene;<br><br> 25<br><br> (v) -MC^alkylene or C,^alkyleneMC,^alkylene, wherein M is O, S, or -NR2 wherein R2 represents hydrogen or C| 3alkyl;<br><br> (vi) a 5- or 6- membered heterocyclic group containing 3t least one nitrogen 30 heteroatom and optionally at least one further heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by C, 3 alkyl; and<br><br> Printed from Mimosa<br><br> WO 97/31907<br><br> PCT/EP97/D0916<br><br> 136<br><br> (vii) Het-C^alkylene, wherein Het represents a heterocyclic group r s defined in point (vi) above;<br><br> Alk represents C, 3alkylene;<br><br> R1 represents hydrogen or C, 3 alkyl;<br><br> Z is selected from the group consisting of:<br><br> (viii) -(C, 3alkylene) phenyl, which phenyl is optionally substituted by one or more halogen atoms; and<br><br> (ix) -NR3R\ wherein R3 represents hydrogen or C13 alkyl, and R4 represents -Y-(C=0)-T-R5 , or -Y-(CH(OH))-T-R5, wherein:<br><br> (a) Y represents a bond, C1-6 alkylene, C2&lt; alkenylene, cycloalkylene or cycloalkenylene, a heterocyclic group as defined in point (vi) above, or phenyl optionally substituted by one or more C, 3 alkyl groups and/or one or more halogen atoms;<br><br> (b) T represents a bond, C13 alkyleneoxy, -0- or -N(R6)-, wherein R6 represents hydrogen or CV3 alkyl;<br><br> (c) R5 represents alkyl, C^g cycloalkyl or cycloalkenyl, phenyl (optionally substituted by one or more: halogen atoms, C,3 alkyl, C13 alkoxy groups, Co.3alkyleneNR9R10 where each R9 and R10 is independently hydrogen, 0^.3 alkyl, •S02C^.3alkyl, or "COjC^jSlkyl! -SO^NHC ^, Cq.j alkyleneC02H, Co.3 alkyteneC02C1.3alkyl, or -0CH2C(0)NH2), a 5- or 6-membered heterocyclic group as defined in point (ii) above,<br><br> Printed from Mimosa<br><br> 137<br><br> or a bicylic fused ring | d wherein ring D represents a 5- or 6-<br><br> membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by (=0), which bicyclic ring is attached to T via a ring atom of ring D, or -C^aikyleneMR11 M<br><br> is 0, S, or -NR2 wherein R2 and R" are independently hydrogen or C13 alkyl;<br><br> or a tautomeric form thereof, and/or a pharmaceutically acceptable salt or solvate 10 thereof.<br><br>
  2. 2. Tne compound of Claim 1 wherein each of said 5- or 6- membered heterocyclic groups is independently selected from the group consisting of substituted or unsubstituted imidazolidinyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl,<br><br> 15 pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, or tetrazolyl.<br><br>
  3. 3. A compound according to claim 1 or 2 wherein A represents phenyl, pyridyl, piperazinyl or benzoxazolyl any of which is optionally substituted by one or more C,.3<br><br> 20 alkyl.<br><br>
  4. 4. A compound according to claim 3, wherein A represents phenyl, piperazinyl or pyridyl.<br><br> 25
  5. 5. A compound according to claim 1, 3 or 4 wherein B represents C,_3 alkylene, N(CH3) Cv3 alkylene or Het-C^ alkylene wherein Het represents a 5-membered heterocyclic group containing at least one nitrogen atom and optionally at least one further heteroatom selected from oxygen and sulphur, substituted or unsubstituted by Cvz alkyl.<br><br> 30<br><br> intellectual property office of nz<br><br> 27 MAR 2000 RECEIVED<br><br> 1<br><br> 138<br><br> $81<br><br>
  6. 6. A compound according to claim 5 wherein B represents N(CH3)(CH2)2,<br><br> oxazolyl-C-^-alkylene wherein said oxazolyl is optionally substituted by C-,.3 alkyl, or thiazolyl which is optionally substituted by C^.3 alkyl.<br><br>
  7. 7. A compound according to any preceding claim, wherein Alk represents methylene.<br><br>
  8. 8. A compound according to any preceding claim, wherein R1 represents hydrogen, methyl or ethyl.<br><br>
  9. 9. A compound according to claim 8, wherein R1 is hydrogen.<br><br>
  10. 10. A compound according to any preceding claim, wherein Z represents NR3R4 wherein R3 and R4 are as defined in claim 1.<br><br>
  11. 11. A compound according to claim 10 wherein R3 is hydrogen.<br><br>
  12. 12. A compound according to claim 10 or 11, wherein R4 represents -Y-(C=0)-T-R5 wherein Y, T and R5 are as defined in claim 1.<br><br>
  13. 13. A compound according to claim 12 wherein Y is phenyl optionally substituted by one or more C,_3 alkyl groups and/or one or more halogen atoms.<br><br>
  14. 14. A compound according to claim 12 or 13 wherein T is a bond or -O-.<br><br>
  15. 15. A compound according to claim 12, 13 or 14 wherein R5 represents C,_3 alkyl or phenyl (optionally substituted by one or more halogen atoms or one or more C,_3 alkyl groups).<br><br>
  16. 16. A compound of claim 10 wherein Z represents NR3R4 wherein R3 represents H and R4 represents -Y-(C=0)-T-R5, said NH and said (CO) are positioned ortho to each other on Y (which is phenyl), T is a bond or -0-, R5 is alkyl, or phenyl (optionally substituted by one or more: halogen atoms, C1, alkyl, C13 alkoxy groups, Co_3alkyleneNR9R10 where each R9 and R10 is independently hydrogen, CM alkyl, -S02C1.3alkyl, or -C02C1.3alkyl, -S02NHC1.3alkyl, Cq.3 alkyleneC02H, Co.3 alkyieneC02C1.3alkyl, or -0CH2C(0)NH2).<br><br> ih1b1ectuai property office OF HZ<br><br> 27 MAR 2000<br><br> 139<br><br>
  17. 17. A compound according to claim 15 or 16 wherein R4 represents wherein R13 is phenyl or OCH3 .<br><br>
  18. 18. A compound according to claim 1 of formula 1(a)<br><br> a-b-0<br><br> (1a)<br><br> 10<br><br> wherein A and B are as described in claim 1 and Ar represents a phenyl or a 5 or 6 membered heteoaryl group containing at least the heteroatom selected from oxygen, nitrogen and sulphur and solvates thereof.<br><br> 15
  19. 19. A compound according to claim 1 having the formula (I):<br><br> a — b—o—<br><br> (i)<br><br> wherein<br><br> 20 A is selected from the group consisting of:<br><br> (i) phenyl optionally substituted by one or more halogen atoms;<br><br> 25<br><br> (ii) a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and intellectual property office of n2.<br><br> - 1 MAY 2000<br><br> WO 97/31907 PCT/EP97/00916<br><br> 140<br><br> a fused bicyclic ring c wherein ring C represents a heterocyclic group as defined in (ii) above, which bicyclic ring is attached to group B via a ring atom of ring C;<br><br> 5 B is selected from the group consisting of:<br><br> (iv) alkylene;<br><br> (v) -NF^C^alkylene, wherein R2 represents hydrogen or C,.3 alkyl;<br><br> 10<br><br> (vi) a 5- or 6- membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by C13 alkyl; and<br><br> 15 (vii) Het-C^alkylene, wherein Het represents a heterocyclic group as defined in point (vi) above;<br><br> Alk represents C13alkylene;<br><br> 20 R1 represents hydrogen or C13 alkyl;<br><br> Z is selected from the group consisting of:<br><br> (viii) -(C13alkylene) phenyl, which phenyl is optionally substituted by one or more 25 halogen atoms; and<br><br> (ix) -NR3R\ wherein R3 represents hydrogen or C13 alkyl, and R4 represents -Y-(C=0)-TR5 , or -Y-(CH(OH))-T-R5, wherein:<br><br> 30 (a) Y represents a bond, alkylene, C2^ alkenylene, C4^ cycloalkylene or cycloatkenyiene, a heterocyclic group as defined in point (vi) above, or phenyl optionally substituted by one or more C13 alkyl groups and/or one or more halogen atoms;<br><br> Printed from Mimosa<br><br> WO 97/31907<br><br> PCT/EP97/00916<br><br> 141<br><br> (b) T represents a bond, C13 alkyleneoxy, -0- or -N(R6)-1 wherein R6 represents hydrogen or C13 alkyl;<br><br> (c) R5 represents C,^ alkyl, cycloalkyl or cycloalkenyl, phenyl optionally substituted by one or more halogen atoms or one or more C, 3 alkyl groups, a 5- or 6- membered heterocyclic group as defined in point (ii) above,<br><br> membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by (=0), which bicyclic ring is attached to T via a ring atom of ring D,<br><br> or a tautomeric form thereof, and/or a pharmaceutically acceptable salt or solvate thereof.<br><br>
  20. 20. A compound as claimed in claim 1 which is selected from the group consisting of.<br><br> 3-(4-Benzyloxy-phenyl)-2(SM1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid dicyclohexylamine salt<br><br> 3-(4-Benzyloxy-phenyl)-2(S)-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid methyl ester<br><br> 2(SH2-3enzoyl-cyc!ohex-1 -enylamino)-3-(4-benzyloxy-phenyl)-propionic acid dicydohexylamine salt<br><br> 2-(2-benzoylphenylamino)-3-(4-benzyloxyphenyl) propanoic acid<br><br> 3-(4-Benzyloxy-phenyl)-2-(2-benzyloxy-phenylamino)-propionic acid methyl ester 3-(4-Benzyloxy-phenyl)-2-(phenylcarbamoyl-phenylamino)-propionic acid methyl ester<br><br> 3-(4-Benzyloxy-phenyl)-2-[2-(piperidine-1-carbonyl)-phenylamino]-propionic acid methyl ester<br><br> 2-(3-Benzoyl-thiophen-2-yl-am»no)-3-(4-benzyloxy-phenyl)-propionicacid 2-(2-Benzoyl-thiophen-3-yl-amino)-3-(4-benzyloxy-phenyl)-propionic acid wherein ring D represents a 5- or 6-<br><br> Printed from Mimosa<br><br> WO 97/31907<br><br> PCT/EP97/00916<br><br> 142<br><br> 3-(4-BenzykJxy-phenyl)-2(S)-((4-oxo-4H-chromene-3-carbonyl)-amino]-propionic acid methyl ester.<br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid<br><br> 5 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(methyl-pyndin-2-yl-amino)ethoxy]-phenyf}-propionic acid<br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid ethyl ester<br><br> 2-(1-Methyl-3-oxo-3-phenyl-propenylamino)-3{4-[2-(methyl-pyridin-2-yl-amino)-10 ethoxy}-phenyl}-propionic acid dicyclohexylamine salt<br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-pheny!amino)-propionic acid<br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-phenylamino)-propionic acid<br><br> 15 3-{4-{2-(Benzoxazol-2yl-methyl-amino)-ethoxy]-phenyl)-2(S)-(1-methyl-3-oxo-3-phenyl-propenylamno)-propionic acid dicyclohexylamine salt 3-{4-{2-&lt;Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2(S)-[3-(3-iodo-phenyl)-1-methyl-3-oxo-propenylamino]-propionic acid dicyclohexyl-amine salt 3-{4-{2-(benzoxazol-2-yl-methyl-amino)-€thoxy]-phenyI}-2-{2-benzoyl-4-methyl-20 phenylamino)-propionic acid<br><br> 3-{4-{2-(benzoxazol-2-yl-methyt-amino)-ethoxy]-phenyl}-2-(2-benzoyl-4-chloro-phenylamino)-propk)nic acid<br><br> 3-{4-(1-Benzoxazol-2-yl-pyrroltdin-3-yloxy)-phenyl]-2-(2-benzoyl-phenylamino)-propionic acid<br><br> 25 3-{4-(1-benzoxazol-2-yl)-pyrrolidin-2R-yl-methoxy)-phenylJ-2-(2-benzoyl-phenylamino)-propionic acid<br><br> 3-[4-( 1 -benzoxazol-2-yl)-pyiTolidin-2S-yl-methoxy)-phenyl]-2-(2-benzoyl-phenylamino)-propionic acid<br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxyJ-phenyl}-2-(2-cyclohexanecarbonyl-30 phenylamino)-propionic acid<br><br> 3-{4-[2-Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-thiophen-3-ylamino)-propionic acid.<br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy}-phenyl)-2-benzyl-propionic acid trifluoroacetate.<br><br> Printed from Mimosa<br><br> 3-{4-[2-(Benzoxazol-2-y!-methyl-amino)-ethoxy]-phenyl}-2-(2-bromo-benzyl)-propionic acid trifluoroacetate.<br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2(S)-[(4-oxo-4H-chromene-3-carbonyl)-amino]-propionic acid. 5 2(S)-(2-Benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2-(2-Benzoyl-pheny!amino)-3-{4-[2-(4-chlorophenyl)-thiazol-4ylmethoxy]-phenyl}-propionic acid<br><br> 3-[4-(2-Benzoimidazol-1-yl-ethoxy)-pheny!]-2-(2-benzoyl-phenylamino)-propionic 10 acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(4-methoxy)-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(4-fluoro)-pheriyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid 15 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(5-methyl-thien-2-yl)-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-1-phenyl-1H-pyrazol-3-yl)-ethoxy]-Dhenylj-propionic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-piperidin-1-yl-oxazol-4-yl)-ethoxy]-20 phenyl}-propionic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-morpholin-4-yl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(4-pyridyl)-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid '25 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(2-dimethylamino-5-methyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-(5-methyl-isoxazol-3-yl)-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-methyl-2-(4-methyl[1,2&gt;3]thiadiazol-5-yl)-30 thiazol-4-yl]-ethoxy}-phenyl)-prcpionic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-methyl-2-(4-methyl-piperazin-1-yl)- thiazol-<br><br> 4-yl]-ethoxy}-pheny!)-propionic acid<br><br> INTELLECTUAL PROPERTY OFFICE OF N2.<br><br> 2 8 APR 2000 RECEIVED<br><br> 144<br><br> 2-(1-Carboxy-2-{4-[2-(5-methyl-2-phenyl-th!3zol-4-yi)-ethoxy]-phenyl}-ethylamino)-<br><br> benzoic acid methyl ester<br><br> 2-( 1 -Carboxy-2-{4-[2-(4-chloraphenylsulfanyl)-ethoxy]-phenyl}-ethyiamino)- benzoic acid methyl ester<br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-cyclopentanecarbonyl-phenylamino)-propionic acid<br><br> 3-{4_[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-cyclohexanecarbonyi-5-fluoro-phenylamino)-propionic acid<br><br> 3-{4-[2-(Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(4-cyclohexanecarbonyl-<br><br> 2-methyl-2 H-pyrazol-3-ylamino)-propionic acid<br><br> 3-{4-[2-(Benzoxazol-2-yi-methyi-amino)-ethoxy]-phenyl}-2-(3-benzoyl-thiophene-2-ylamino)-propionic acid<br><br> 2-(2-Cyclohexanecarbonyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2-(2-Cyclohexanecarbonyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 3-[4-(1-Benzoxazol-2-yl-pyrrolidin-3-yloxy)-phenyl]-2.-(2-benzoyl-phenylamino)-propionic acid<br><br> 3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2(S)-[2-(pyridine-4-carbonyl)-phenylamino]-propionic acid<br><br> 3-{4-[2-(5-methyi-2-phenyl-oxazol-4-yl)-ethoxy]-pheny!}-2(S)-[2-(pyridineN-oxide-4-carbonyl)-phenylamino]-propionic acid<br><br> 3-{4-[2-(5-Methyi-2-phenyl-oxazol-4-yl)-ethoxy]-phenyi}-2(S)-[2-(pyndine-3-carbonyl)-phenylamino]-propionic acid<br><br> 3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethcxy]-phenyl}-2(S)-[2-(pyridine-N-oxide-3-carbonyl)-phenylamino]-propionic acid<br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyi-3-phenyl-pyrazoi-1-yl)-ethoxy]-phenyi}-propionic acid<br><br> INTtOfcCTUAL PROPERTY OFFICE OF N.Z.<br><br> 2 8 APR 2000 RECEIVED<br><br> 331381<br><br> 145<br><br> 2S-(2-benzoyl-phenylamino)-3-[4-(1-pyridin-2-yl-pyrrolidin-2S-yl-methoxy)-phenyl]-propionic acid<br><br> 2S-(2-benzoyl-pbenylamino)-3-{4-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-ethoxy]-phenyl}-propionic acid 5 2S-(2-benzoyl-phenylamino)-3-{4-[2-(3-furan-2-yl-5-methyl-pyrazol-1-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-3-phenyl-[1,2,4]triazol-1-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(3-methoxymethyl-5-methyl-2-phenyl-3H-10 imidazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-3H-imidazol-4-yl)-ethoxy]-phenyl}-propionic acid hydrochloride salt<br><br> 2S-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 15 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-{3-methyi-thien-2-yl)-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2(S)-(2-{4-[2-(5-chloro-2-pyridylsuifanyl)-ethoxy]-phenyl}-1-methoxycarbonyl-ethylamino)-benzoic acid<br><br> 2(S)-(2-{4-[2-(N-ethyl-2-methyl-toiuidino)-ethoxy]-pheny!}-1-methoxycarbonyl 20 ethylamino)-benzoic acid<br><br> 3-[4-(3-Benzoxazol-2-yi-thiazolidin-4(R)-yimethoxy)-phenyl]-2(S)-(2-benzoyl-phenylamino)-propionic acid<br><br> 3-{4-[2-(benzoxazol-2~yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(4-trifluorornethyl-benzoyl)-phenylamino-propionic acid 25 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(2-thiophenecarbonyl)-phenylamino-propionic acid<br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(3-thiophenecarbonyl)-phenyiamino-propionic acid<br><br> 30<br><br> INTELLECTUAL PROPERTY OFFICE OF N.Z.<br><br> 2 8 apr 2000 received<br><br> 146<br><br> 33 1381<br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(3-methoxy-benzoyl)-phenylamino-propionic acid<br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-pheny[}-2-[2-(2-methoxy-benzoyl)-phenylamino-propionic acid 5 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(3-methyl-benzoyl)-phenylarnino-propionic acid<br><br> 2-[2-(4-dimethylaminomethyl-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propicnic acid hydrochloride<br><br> 2-[2-(4-aminomethyl-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-10 ethoxy]-phenyl}-propionic acid hydrochloride<br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-[2-(2,6~dimethylbenzoyl)-phenylamino-propionic acid<br><br> 3-(2-{1-carboxy-2-[4-(2-{5-methyl-2-phenyl-oxazol-4-yl}-ethoxy)-phenyl]-ethylamino}-benzoyl benzoic acid<br><br> 15 2-[2-(3-aminomethyl-benzoy!)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid hydrochloride<br><br> 2-[2-'3-dimethylaminomethyl-benzoy!)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazoi-4-yl)-ethoxy]-phenyl}-propionic acid hydrochloride 2-(1-carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethylamino)-20 benzoic acid methyl ester<br><br> 2-(1-carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethyiamino)-benzoic acid 2-am:noethyl amide hydrochloride<br><br> 2-(1-carboxy-2-{4-{2-(5-methyl-2-ohenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethylamino)-benzoic acid methyl amide 25 3-{^-[2-(5-methyl-2-phenyi-oxazoi—-yr.-ethoxy]-phenyl}-2-[2-(4-propylsulfamoyl-benzoyl)-phenylamino]-propionic acid<br><br> 30<br><br> INTELLECTUAL PROPERTY OFFICE OF N.Z.<br><br> 2 8 apr 2000<br><br> i received<br><br> 33 1381<br><br> 2-[2-{3-methanesulfonylamino-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2-[2-(3-methoxycarbonylamino-benzoyl)-phenylamino]-3-{4-[2-(5-methyl-2-phenyl-ox izol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 5 2-[2-(3-carbanoylrnethoxy-benzoyl)-phenylamino]-3-{4-[2-(5-methyi-2-phenyl-oxazol-4-yl)-ethoxy]-pheny!}-propionic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-pyridin-4-yl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2(S)-(2-benzoyl-phenyiamino)-3-(4-{2-[5-methyl-2-(4-methyl-piperazin-1-yl)-thiazoi-4-10 yl]-ethoxy}-phenyl)-propionic acid hydrochloride<br><br> 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-methyl-2-(4-tert-butoxycarbonyl-piperazin-1-y!)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-piperazin-1-yl-thiazoi-4-yl)-ethoxy]-phenyl}-propionic acid 15 2(S)-(2-benzoyl-phenylamino)-3-(4-{2-[5-methyl-2-(4-methylsulfonyl-piperazin-1 -yl)-thiazol^4-yl]-ethoxy}-phenyl)-propionic acid<br><br> 2(S)-(1-carboxy-2-{4-[2-(4-dimethylamino-phenyl)-ethoxy]"phenyl}-ethylamino)-benzoic acid methyl ester<br><br> 2(S)-[1-methoxycarbonyl-2-(4-{2-[5-methyl-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-20 ethoxy}-phenyl)-ethylamino]-benzoic acid<br><br> 2(S)-(1-carboxy-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethylamino)-benzoic acid methyl ester<br><br> 2(S)-(1-carboxy-2-{4-[2-(4-trifluoromethoxy-phenyl)-ethoxy]-phenyl}-ethylamino)-benzoic acid methyl ester 25 3-{4-[2-{Benzoxazol-2-yl-methylamino)-ethoxy]-phenyl}-3-(4-benzoyl-thienyiamino)-propionic acid<br><br> 3-{4_[2-(Benzo\3Zol-2-yl-methyiamino)-ethoxy]-phenyl}-2-(2-(4-methoxy-benzoyi)-phenylamino)-propionic acid<br><br> 3_[4-[2-(Benzoxazol-2-yl-methylamino)-ethoxy]-phenyl}-2-(2-(4-methyl-benzoyl)-30 phenylamino)-propionic acid<br><br> 3-{4-[2-(Benzoxazol-2-yl-methylamino)-ethoxy]-phenyl}-2-(2-(2<br><br> 35<br><br> INTELLECTUAL PROPERTY OFFICE OF N.Z.<br><br> 2 8 apr 2000 RECEIVED<br><br> 148<br><br> f<br><br> 381<br><br> -methyl-benzoyl)-phenylamino)-propionic acid<br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-propionic acid 2-(2-Benzoyl-phenylamino)-3-{4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-phenyl}-propionic acid propionic acid<br><br> 2-(2-Benzoyl-phenylamino)-3-[4-(4-isopropyl-benzyloxy)-phenyl]~propionic acid 2-(2-Benzoyl-phenylamino)-3-[4-(4-chloro-benzyloxy)-phenyl]-propionic acid 2-(2-Benzoyl-phenylamino)-3-{4-[3-(4-methoxy-phenyl)-propoxy]-phenyl}-propionic acid<br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(4-dimethylamino-phenyl)-ethoxy]-phenyl}-propionic acid<br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(4-bromo-phenoxy)-ethoxy]-phenyl}-propionic acid<br><br> 2-(2-Benzoyl-phenylamino)-3-(-4-{2-[3-(6-methyl-pyridin-2-yl)-propoxy]-ethoxyl}-phenyl)-propionic acid<br><br> 2-{2-Benzoyl-phenylamino)-3-[4-(2-pyridin-3-yl-ethoxy]-phenyl]-propionic acid 2-(2-Benzoyl-phenylamino)-3-{4-[2-(3-methyl-6-oxo-6H-pyridazin-1-yl)-ethoxy]-phenyl}-propionic acid<br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(4-trifluoromethoxy-phenyl)- ethoxy]-phenyl}-propionic acid<br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(3-cyano-phenoxy}-ethoxy]-phenyl}-propionic acid<br><br> 2-(2-Benzoyl-phenylamino)-3-{4-[2-(6-methoxy-pyridin-2-ylsulfanyl)-ethoxy]-phenyl}-propionic acid.<br><br>
  21. 21. A compound as claimed in claim 20 which is selected from the group consisting of:<br><br> 2( S)- (1 -carboxy-2-{4-{2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-ethylamino)-benzoic acid methyl ester<br><br> 2-(2-Benzoyl-phenylamino)-3-{4-2[-(4-chloro-phenylsuifanyl)ethoxy]-<br><br> phenyl}-<br><br> INTELIECTUAL PROPERTY OFFICE OF N2.<br><br> 2 8 APR 2000<br><br> RECEIVED<br><br> 149<br><br> MUSi<br><br> 3-{4-[2-(benzoxazol-2-yl-methyl-amino)-etho:;y]-phenyl}-2(SH2-benzoyl-phenylamino)-propionic acid;<br><br> 3-{4-[2-(Benzoxazoi-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-cyclohexanecarbonyl-phenylamino)-propionic acid;<br><br> 3-{4-[2-Benzoxazol-2-yl-methyl-amino)-ethoxy]-phenyl}-2-(2-benzoyl-thiophen-3-ylamino)-propionic acid.<br><br> 2(S)-[1-methoxycarbonyl-2-(4-{2-[5-methyl-2-(4-methyi-piperazin-1-yl)-thiazol-4-yl]-ethoxy}-phenyl)-ethylamino]-benzoic acid<br><br> 2(S)-(2-benzoyl-phenylamino)-3-{4-[2-(nethyl-pyridin-2-yl-amino)-ethoxy]-phenyl}-propionic acid;<br><br> 2(S)-(2-Benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;<br><br> and pharmaceuticaily acceptable salts and solvates thereof.<br><br>
  22. 22. A pharmaceutical composition comprising a compound according to any of Claims 1-21 or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable carrier.<br><br>
  23. 23. A compound according to any of claims 1-21 for use in therapy.<br><br>
  24. 24. Use of a compound according to any of claims 1-21 for the manufacture or a medicament for the treatment of a PPAR-gamma mediated disease.<br><br>
  25. 25. Use of a compound according tc any of claims 1-21 for the manufacture of a medicament for the treatment of individuals requiring lower blood glucose levels.<br><br>
  26. 26 Use of a compound according to any of claims 1-21 for the manufacture of a medicament for the treatment of hyperglycaemia, dyslipidemia, Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperiipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, and cardiovascular disease, especially atherosclerosis.<br><br> intellectual property office 0FN2.<br><br> 2? MAR 2000 RCrCMItn<br><br> 150<br><br>
  27. 27. A method for the preparation of compounds according to Claim 1 comprising the step of reacting a compound of Formula A-B-X with a compound of Formula (II)<br><br> (M)<br><br> wherein A, B, alk, R1, and Z are as defined in Claim 1 and B comprises a C^<br><br> alkylene group and X is a leaving group or a hydroxyl group.<br><br>
  28. 28. The method ot Claim 27 wherein X is a hydroxyl group, a halide, or an alkyl- or aryl-sulfonyloxy group, A is phenyl, pyridyl, or benzoxazolyl, B is said Het-C-,. eAlkylene, and Z is -NH -Y(C=0)-T-R5 wherein Y is phenyl optionally substituted by one or more C13 alkyl groups and/or one or more halogen atoms, T is a bond or -0-, and R5 is C^ alkyl, or phenyl (optionally substituted by one or more halogen atoms, C13 alkyl, C13 alkoxy groups, C0.3alkyleneNR9R10 where each R9 and R'° is independently hydrogen, C-,_3 alkyl, -S02C1.3alkyl, or -C02C-,.3alkyl, -S02NHC1.3alkyl, Cq.3 alkyleneC02H, Co-aalkyleneCC^C^alkyl, or -0CH2C(0)NH2).<br><br>
  29. 29. The method of Claim 27 or 28 wherein R1 is hydrogen and X is a halide, or an alkyl- or aryl-sulfonyloxy group.<br><br>
  30. 30. The method of Claim 29 wherein said A-B-X and said compound of Formula (II) are:<br><br> wherein OMs is a mesylate leaving group and R13 is a phenyl or -OCH3 group.<br><br> intellectual property office<br><br> OF N.Z.<br><br> - 1 may 2000 received<br><br> 151<br><br> 33 13 8 |<br><br>
  31. 31. The method of Claim 27 or 28' \ ierein R' is a C3alkyl and X is a hydroxyl group.<br><br>
  32. 32. The method of Claim 31 wherein said reaction comprises a Mitsunobu reaction followed by hydrolysis of the depicted aikyl ester group to the corresponding acid without isolation of the ester.<br><br>
  33. 33. The method of Claim 32 wherein said Mitsunobu reaction is carried out in a reaction mixture comprising toluene.<br><br>
  34. 34. The method of any of Claims 31-33 wherein said A-B-X and said compound of Formula (II) are:<br><br> Wherein R13 is a phenyl or -OCH3 group.<br><br>
  35. 35. The method of Claim 27 or 28, wherein in the compound of Formula (II), Z is and wherein the compound of Formula (II) is prepared comprising the steps of first preparing a compound of Formula (II) wherein Z is<br><br> INTELLECTUAL PROPERTY OFFICE OF N2.<br><br> 27 m 2000<br><br> RECEIVED<br><br> $3:# f.<br><br> followed by the step of dehydrogenating with a dehydrogenation catalyst in the presence of a hydrogen acceptor.<br><br>
  36. 36. The method of Claim 35 wherein said hydrogen acceptor is an aromatic nitro compound.<br><br> INTELLECTUAL PBOPfflTY OFFICE OFNZ<br><br> 27 MAR 2000 RECEIVED<br><br> </p> </div>
NZ331381A 1996-02-28 1997-02-26 Substituted 4-hydroxy-phenylalcanoic acid derivatives NZ331381A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9604242.9A GB9604242D0 (en) 1996-02-28 1996-02-28 Chemical compounds
PCT/EP1997/000916 WO1997031907A1 (en) 1996-02-28 1997-02-26 Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to ppar-gamma

Publications (1)

Publication Number Publication Date
NZ331381A true NZ331381A (en) 2000-06-23

Family

ID=10789571

Family Applications (1)

Application Number Title Priority Date Filing Date
NZ331381A NZ331381A (en) 1996-02-28 1997-02-26 Substituted 4-hydroxy-phenylalcanoic acid derivatives

Country Status (41)

Country Link
US (1) US6294580B1 (en)
EP (1) EP0888317B1 (en)
JP (1) JP3255930B2 (en)
KR (1) KR100462730B1 (en)
CN (1) CN1093124C (en)
AP (1) AP780A (en)
AR (1) AR011502A1 (en)
AT (1) ATE205485T1 (en)
AU (1) AU717699B2 (en)
BG (1) BG102792A (en)
BR (1) BR9707786B1 (en)
CA (1) CA2247443C (en)
CY (1) CY2319B1 (en)
CZ (1) CZ295383B6 (en)
DE (1) DE69706658T2 (en)
DK (1) DK0888317T3 (en)
EA (1) EA001403B1 (en)
EE (1) EE9800288A (en)
ES (1) ES2163125T3 (en)
GB (1) GB9604242D0 (en)
GE (1) GEP20012580B (en)
HK (1) HK1015369A1 (en)
HR (1) HRP970110B1 (en)
HU (1) HUP0004845A3 (en)
ID (1) ID15985A (en)
IL (1) IL125796A (en)
IS (1) IS1869B (en)
MY (1) MY119425A (en)
NO (1) NO311516B1 (en)
NZ (1) NZ331381A (en)
OA (1) OA10843A (en)
PE (1) PE43098A1 (en)
PL (1) PL191118B1 (en)
PT (1) PT888317E (en)
RS (1) RS49586B (en)
SI (1) SI0888317T1 (en)
SK (1) SK282753B6 (en)
TR (1) TR199801707T2 (en)
UA (1) UA58502C2 (en)
WO (1) WO1997031907A1 (en)
ZA (1) ZA971645B (en)

Families Citing this family (155)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL121202A (en) 1996-07-01 2001-08-26 Lilly Co Eli Hypoglycemic and hypolipidemic compounds, process for their preparation, pharmaceutial compositions comprising same, and uses thereof
EE03765B1 (en) 1996-08-19 2002-06-17 Japan Tobacco Inc. Propionic acid derivatives and their uses
EP1006794B1 (en) 1997-03-12 2007-11-28 Robert W. Esmond A method for treating or preventing alzheimer's disease
EP0903343B1 (en) * 1997-09-19 2003-05-28 SSP Co., Ltd. Alpha-Substituted phenylpropionic acid derivative and medicine containing the same
BR9813019A (en) * 1997-10-02 2000-09-05 Sankyo Co Derivatives of amidocarboxylic acid, agents for lowering blood glucose, reducing lipid, for improving insulin resistance, anti-inflammatory, for immuno-regulation, for inhibiting aldose reductase, for inhibiting 5-lipoxygenase, for the generation of suppressor of lipid peroxide, to activate ppar, to reduce osteoporosis, and compositions for the therapy or prevention of diabetes mellitus, hyperlipemia, obesity, impaired glucose tolerance, insulin resistance other than igt, liver fatty, diabetic complications, arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome, arthroesthesis, rheumatoid arthritis, allergic diseases, asthma, cancer, autoimmune diseases, pancreatitis, and cataracts
US6444816B1 (en) * 1997-10-27 2002-09-03 Dr. Reddy's Research Foundation Fused 7-oxo-pyrimidinyl compounds, preparation, composition and use thereof
US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
US6583157B2 (en) 1998-01-29 2003-06-24 Tularik Inc. Quinolinyl and benzothiazolyl modulators
AU759255B2 (en) 1998-01-29 2003-04-10 Amgen, Inc. PPAR-gamma modulators
WO1999043642A1 (en) 1998-02-26 1999-09-02 Celltech Therapeutics Limited Phenylalanine derivatives as inhibitors of alpha4 integrins
GB9805655D0 (en) 1998-03-16 1998-05-13 Celltech Therapeutics Ltd Chemical compounds
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
DE69919156T2 (en) 1998-05-11 2005-11-03 Takeda Pharmaceutical Co. Ltd. OXYIMINOALKANIC ACID DERIVATIVES WITH HYPOGLYKEMIC AND HYPOLIPIDEMIC EFFECT
GB9811159D0 (en) 1998-05-22 1998-07-22 Celltech Therapeutics Ltd Chemical compounds
GB9811969D0 (en) 1998-06-03 1998-07-29 Celltech Therapeutics Ltd Chemical compounds
SE9801992D0 (en) 1998-06-04 1998-06-04 Astra Ab New 3-aryl-2-hydroxypropionic acid derivative I
MA26634A1 (en) 1998-06-04 2004-12-20 Astra Ab NOVEL 3-ARYL PROPIONIC ACID DERIVATIVES AND THE LIKE
SE9801990D0 (en) * 1998-06-04 1998-06-04 Astra Ab New 3-aryl propionic acid derivatives and analogs
ATE274510T1 (en) * 1998-06-19 2004-09-15 Chiron Corp GLYCOGEN SYNTHASE KINASE 3 INHIBITORS
GB9814414D0 (en) 1998-07-03 1998-09-02 Celltech Therapeutics Ltd Chemical compounds
GB9817118D0 (en) * 1998-08-07 1998-10-07 Glaxo Group Ltd Pharmaceutical compounds
GB9821061D0 (en) * 1998-09-28 1998-11-18 Celltech Therapeutics Ltd Chemical compounds
GB9821222D0 (en) 1998-09-30 1998-11-25 Celltech Therapeutics Ltd Chemical compounds
US6589969B1 (en) 1998-10-16 2003-07-08 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivatives and drugs containing the same as the active ingredient
GB9825652D0 (en) 1998-11-23 1999-01-13 Celltech Therapeutics Ltd Chemical compounds
GB9826174D0 (en) 1998-11-30 1999-01-20 Celltech Therapeutics Ltd Chemical compounds
JP2002532416A (en) * 1998-12-17 2002-10-02 マインドセット・バイオファーマシューティカルズ・（ユーエスエイ）・インコーポレイテッド Enhancing brain glucose utilization
US6127394A (en) * 1999-03-08 2000-10-03 The University Of Mississippi 1,2-Dithiolane derivatives
US6204288B1 (en) 1999-03-08 2001-03-20 The University Of Mississippi 1,2-dithiolane derivatives
CZ20013593A3 (en) 1999-04-06 2002-03-13 Sankyo Company, Limited Alpha-substituted derivatives of carboxylic acids
RU2001130883A (en) * 1999-04-16 2004-03-20 Др. Редди`З Лабораториз Лимитед (In) NEW POLYMORPHIC FORMS OF ANTI-DIABETIC AGENT, METHOD FOR PRODUCING THERE AND THEIR PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US6528507B1 (en) 1999-04-16 2003-03-04 Dr. Reddy's Laboratories Limited Polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them
AU3957800A (en) * 1999-04-16 2000-11-02 Dr. Reddy's Research Foundation Crystalline r- guanidines, arginine or (l) -arginine (2(s)) -2- ethoxy -3-(4- (2-(10(h) -phenoxazin -10-yl)ethoxy}phenyl)propanoate
ATE299861T1 (en) * 1999-04-19 2005-08-15 Coelacanth Corp PPAR (GAMMA) AGONISTS FOR THE TREATMENT OF TYPE II DIABETES
IL145789A0 (en) * 1999-04-20 2002-07-25 Novo Nordisk As Derivatives of propionic acid, their preparation and pharmaceutical compositions containing them
US6274608B1 (en) 1999-04-20 2001-08-14 Novo Nordisk A/S Compounds, their preparation and use
US7414128B2 (en) 1999-04-20 2008-08-19 Dr. Reddy's Laboratories, Limited Crystalline R-guanidines, Arginine or (L)-Arginine (2S)-2-Ethoxy-3-{4-[2-(10H -phenoxazin-10-yl)ethoxy]phenyl}propanoate
US6972294B1 (en) 1999-04-20 2005-12-06 Novo Nordisk, A/S Compounds, their preparation and use
JP2002542237A (en) * 1999-04-20 2002-12-10 ノボ ノルディスク アクティーゼルスカブ New compounds, their production and use
US6369055B1 (en) 1999-04-20 2002-04-09 Novo Nordisk A/S Compounds, their preparation and use
AU3958100A (en) * 1999-04-20 2000-11-02 Novo Nordisk A/S New compounds, their preparation and use
KR100693771B1 (en) * 1999-04-28 2007-03-12 사노피-아벤티스 도이칠란트 게엠베하 Tri-aryl acid derivatives as PPAR receptor ligands and pharmaceutical compositions containing the same
WO2000066572A1 (en) * 1999-04-28 2000-11-09 Dr. Reddy's Research Foundation Substituted bicyclic heterocycles, process for their preparation and their use as antiobesity and hypocholesterolemic agents
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
JP4618845B2 (en) * 1999-06-09 2011-01-26 杏林製薬株式会社 Substituted phenylpropionic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) alpha agonists
GB9913782D0 (en) * 1999-06-14 1999-08-11 Smithkline Beecham Plc Novel compounds
GB9914977D0 (en) * 1999-06-25 1999-08-25 Glaxo Group Ltd Chemical compounds
US7041691B1 (en) 1999-06-30 2006-05-09 Amgen Inc. Compounds for the modulation of PPARγ activity
NZ516455A (en) * 1999-06-30 2004-03-26 Tularik Inc Compounds for the modulation of PPARgamma activity
US6417212B1 (en) 1999-08-27 2002-07-09 Eli Lilly & Company Modulators of peroxisome proliferator activated receptors
ATE316071T1 (en) * 1999-09-17 2006-02-15 Kyorin Seiyaku Kk O-ANISAMIDE DERIVATIVES
TW200528436A (en) * 1999-09-22 2005-09-01 Bristol Myers Squibb Co Substituted acid derivatives useful as antiodiabetic and antiobesity agents and method
US6414002B1 (en) 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
EP1939188A1 (en) * 1999-09-22 2008-07-02 Bristol-Myers Squibb Company Oxa-and thiazole derivatives useful as antidiabetic and antiobesity agents
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
RU2256661C2 (en) * 1999-12-03 2005-07-20 Киото Фармасьютикал Индастриз, Лтд. Derivatives of tetrahydroisoquinoline and their salts and pharmaceutical composition based on thereof
SE9904415D0 (en) * 1999-12-03 1999-12-03 Astra Ab New process
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
JP4316787B2 (en) * 2000-01-11 2009-08-19 壽製薬株式会社 An ether or amide derivative, a process for producing the same, and a therapeutic agent for diabetes containing the same,
JP2001261674A (en) * 2000-03-22 2001-09-26 Mitsui Chemicals Inc Benzothiophene derivative and intranuclear receptor agonist
AU2001248553A1 (en) 2000-04-17 2001-10-30 Celltech R And D Limited Enamine derivatives as cell adhesion molecules
AU6118001A (en) 2000-05-03 2001-11-12 Tularik Inc Combination therapeutic compositions and methods of use
FR2808798A1 (en) * 2000-05-09 2001-11-16 Hoechst Marion Roussel Inc New N-heterocyclyl-aminoacid derivatives and analogs, are vitronectin analogs useful e.g. for treating osteoporosis, tumor growth or metastasis, inflammation or cardiovascular disease
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
GB0014969D0 (en) 2000-06-19 2000-08-09 Smithkline Beecham Plc Novel method of treatment
AU2001267753A1 (en) 2000-07-07 2002-01-21 Celltech R And D Limited Squaric acid derivatives containing a bicyclic heteroaromatic ring as integrin antagonists
WO2002010136A1 (en) 2000-08-02 2002-02-07 Celltech R & D Limited 3-substituted isoquinolin-1-yl derivatives
WO2002013864A1 (en) * 2000-08-16 2002-02-21 Sankyo Company, Limited Medicinal compositions for preventing and treating cancer
ES2295200T3 (en) 2000-08-23 2008-04-16 Eli Lilly And Company OXAZOLIL-ARILPROPIONIC ACID DERIVATIVES AND ITS USE AS PPAR AGONISTS.
CA2418104A1 (en) * 2000-08-23 2002-02-28 Eli Lilly And Company Oxazolyl-arylpropionic acid derivatives and their use as ppar agonists
AU2001284658A1 (en) * 2000-08-23 2002-03-13 Eli Lilly And Company Oxazolyl-aryloxyacetic acid derivatives and their use as ppar agonists
GB0030845D0 (en) * 2000-12-18 2001-01-31 Smithkline Beecham Plc Novel treatment
KR100635315B1 (en) * 2000-12-25 2006-10-18 오노 야꾸힝 고교 가부시키가이샤 Dihydronaphthalene derivative compounds and drugs containing these compounds as the active ingredient
WO2002051441A1 (en) 2000-12-26 2002-07-04 Sankyo Company, Limited Medicinal compositions containing diuretic and insulin resistance-improving agent
EP1911462A3 (en) 2001-01-26 2011-11-30 Schering Corporation Compositions comprising a sterol absorption inhibitor
US7138390B2 (en) 2001-03-12 2006-11-21 Intercept Pharmaceuticals Steroids as agonists for FXR
WO2002087580A1 (en) * 2001-04-25 2002-11-07 Takeda Chemical Industries, Ltd. Abc expression promoters
SI1392295T1 (en) * 2001-05-15 2006-10-31 Hoffmann La Roche Carboxylic acid substituted oxazole derivatives for use as ppar-alpha and -gamma activators in the treatment of diabetes
AU2002308891B2 (en) 2001-05-29 2007-09-06 Kyoto Pharmaceutical Industries, Ltd. Novel heterocyclic derivatives and medicinal use thereof
EP1403253A4 (en) 2001-05-29 2005-03-30 Kyoto Pharma Ind Novel heterocyclic compound and medicinal use thereof
DE10127126A1 (en) * 2001-06-05 2002-12-19 Forschungszentrum Juelich Gmbh New protected O-(2-substituted ethyl)-L-tyrosine derivatives, useful as intermediates for the positron emission tomography contrast agent O-(2-(18F)-fluoroethyl)-L-tyrosine
KR20040030658A (en) 2001-06-07 2004-04-09 일라이 릴리 앤드 캄파니 Modulators of peroxisome proliferator activated receptors(ppar)
JP2005509590A (en) * 2001-06-07 2005-04-14 イーライ・リリー・アンド・カンパニー Peroxisome proliferator-activated receptor modulators
WO2003011814A1 (en) * 2001-07-30 2003-02-13 Novo Nordisk A/S Novel vinyl n-(2-benzoylphenyl)-l-tyrosine derivatives and their use as antidiabetics etc
US7067530B2 (en) 2001-07-30 2006-06-27 Novo Nordisk A/S Compounds, their preparation and use
WO2003011834A1 (en) * 2001-07-30 2003-02-13 Novo Nordisk A/S Novel vinyl n-(2-benzoylphenyl)-l-tyrosine derivatives and their use as antidiabetics etc
US20030171377A1 (en) * 2001-08-29 2003-09-11 Bigge Christopher Franklin Antidiabetic agents
TW200300681A (en) * 2001-11-12 2003-06-16 Ono Pharmaceutical Co Carboxylic acid derivative compound and medicament containing same as active ingredient
NZ532909A (en) 2001-11-30 2006-08-31 Lilly Co Eli Peroxisome proliferator activated receptor agonists
WO2003053440A1 (en) * 2001-12-11 2003-07-03 Sankyo Company, Limited Medicinal composition
AU2002367154A1 (en) * 2001-12-21 2003-07-15 Smithkline Beecham Corporation Dosing regimen for ppar-gamma activators
EP1466909A4 (en) 2002-01-17 2005-12-07 Toaeiyo Ltd Halogenobenzyl aminopropionic acid derivatives
CA2474353A1 (en) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Method for screening a drug ameliorating insulin resistance
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
US20060148858A1 (en) * 2002-05-24 2006-07-06 Tsuyoshi Maekawa 1, 2-Azole derivatives with hypoglycemic and hypolipidemic activity
JP2004277397A (en) * 2002-05-24 2004-10-07 Takeda Chem Ind Ltd 1, 2-azole derivative
GB0214149D0 (en) * 2002-06-19 2002-07-31 Glaxo Group Ltd Chemical compounds
EP1531810B1 (en) 2002-07-09 2012-02-01 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
WO2004004665A2 (en) 2002-07-09 2004-01-15 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
WO2004037248A2 (en) * 2002-10-24 2004-05-06 Carex Sa Modulation of peroxisome proliferator activated receptors activity
EP2385032A1 (en) 2002-11-08 2011-11-09 Takeda Pharmaceutical Company Limited GPR40 Receptor function regulator
US7268157B2 (en) * 2002-11-26 2007-09-11 Shenzhen Chipscreen Biosciences, Ltd. Substituted arylalcanoic acid derivatives as PPAR pan agonists with potent antihyperglycemic and antihyperlipidemic activity
US6653334B1 (en) 2002-12-27 2003-11-25 Kowa Co., Ltd. Benzoxazole compound and pharmaceutical composition containing the same
EP1597248B1 (en) 2003-02-14 2007-12-26 Eli Lilly And Company Sulfonamide derivatives as ppar modulators
US20060142356A1 (en) * 2003-02-17 2006-06-29 Davis Adrian F Novel therapeutic method and compositions for topical administration
GB0303600D0 (en) * 2003-02-17 2003-03-19 Glaxo Group Ltd Novel therapeutic method and compositions
WO2004101560A1 (en) * 2003-05-13 2004-11-25 Synthon B.V. Processes for making thiazolidinedione derivatives and compounds thereof
KR100796093B1 (en) 2003-07-02 2008-01-21 에프. 호프만-라 로슈 아게 Indolyl derivatives substituted with a thiazole ring and their use as ppar modulators
ATE361294T1 (en) * 2003-08-20 2007-05-15 Lilly Co Eli COMPOUNDS, METHODS AND FORMULATIONS FOR ORAL ADMINISTRATION OF A GLUCAGON-LIKE PEPTIDE (GLP)-1 COMPOUND OR A MELANOCORTIN-4 RECEPTOR (MC4) AGONIST PEPTIDE
EP1658273B1 (en) * 2003-08-20 2007-01-03 Eli Lilly And Company Compounds, methods and formulations for the oral delivery of a glucagon like peptide (glp)-1 compound or an melanocortin 4 receptor (mc4) agonist peptide
US7223761B2 (en) 2003-10-03 2007-05-29 Amgen Inc. Salts and polymorphs of a potent antidiabetic compound
TW200526588A (en) * 2003-11-17 2005-08-16 Smithkline Beecham Corp Chemical compounds
CA2547430A1 (en) 2003-11-26 2005-06-09 Takeda Pharmaceutical Company Limited Receptor function regulating agent
US7321056B2 (en) * 2003-12-15 2008-01-22 Eli Lilly And Company Selective peroxisome proliferator activated receptor modulators
TW200523247A (en) 2003-12-25 2005-07-16 Takeda Pharmaceutical 3-(4-benzyloxyphenyl) propanoic acid derivatives
US7585880B2 (en) 2003-12-26 2009-09-08 Takeda Pharmaceutical Company Limited Phenylpropanoic acid derivatives
EP1725546B1 (en) * 2004-03-09 2008-10-08 F.Hoffmann-La Roche Ag Pyrazolyl indolyl derivatives as ppar activators
US10987362B2 (en) 2004-03-12 2021-04-27 Intercept Pharmaceuticals, Inc. Treatment of fibrosis using FXR ligands
HUE032928T2 (en) 2004-03-12 2017-11-28 Intercept Pharmaceuticals Inc Treatment of fibrosis using Fxr ligands
JP2008508238A (en) 2004-07-30 2008-03-21 ラボラトリオス・サルバト・ソシエダッド・アノニマ Tyrosine derivatives as PPAR gamma modulators
EP1780210A4 (en) * 2004-08-11 2009-06-10 Kyorin Seiyaku Kk Novel cyclic aminobenzoic acid derivative
US7622491B2 (en) * 2004-08-13 2009-11-24 Metabolex Inc. Modulators of PPAR and methods of their preparation
PL371841A1 (en) 2004-12-20 2006-06-26 ADAMED Sp.z o.o. New derivatives of 3-phenylpropionic acid
PL372332A1 (en) * 2005-01-19 2006-07-24 ADAMED Sp.z o.o. New compounds, derivatives of 3-phenylpropionic acid
PL372356A1 (en) 2005-01-20 2006-07-24 ADAMED Sp.z o.o. New compounds, derivatives of 3-phenylpropionic acid
WO2006082495A1 (en) * 2005-02-02 2006-08-10 Ranbaxy Laboratories Limited Peroxisome proliferator activated receptor modulators
ITMI20050912A1 (en) 2005-05-19 2006-11-20 Erregierre Spa PROCESS OF PREPARATION OF ACIDS 3-A-YA (B) -DIDROSSI-6-A (B) -ALCHIL-5B-COLANICI
CA2621164A1 (en) 2005-08-26 2007-03-01 Shionogi & Co., Ltd. Derivative having ppar agonistic activity
WO2007147336A1 (en) * 2006-06-13 2007-12-27 Shanghai Institue Of Materia Medica, Chinese Academy Of Sciences Heterocyclic non-nucleoside compounds, their peparation, pharmaceutical composition and their use as antiviral agents
EP2063890A1 (en) 2006-09-07 2009-06-03 Nycomed GmbH Combination treatment for diabetes mellitus
JP2010502719A (en) 2006-09-08 2010-01-28 ロード アイランド ホスピタル Treatment, prevention and recovery of alcohol-induced brain disease
WO2008091540A2 (en) 2007-01-19 2008-07-31 Intercept Pharmaceuticals, Inc. 23-substituted bile acids as tgr5 modulators and methods of use thereof
JP2008239616A (en) * 2007-02-28 2008-10-09 Iyaku Bunshi Sekkei Kenkyusho:Kk Hdl (high density lipoprotein) enhancer
WO2008117982A1 (en) * 2007-03-28 2008-10-02 Crystal Genomics, Inc. Heterocyclic carboxylic acid derivatives and pharmaceutical composition for inhibiting lipid accumulation containing same
US20160331729A9 (en) * 2007-04-11 2016-11-17 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
ES2438768T3 (en) * 2007-04-11 2014-01-20 Omeros Corporation Compositions and methods for prophylaxis and addiction treatment
US11241420B2 (en) 2007-04-11 2022-02-08 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
EP2154131A4 (en) * 2007-04-26 2011-09-21 Pharmafrontier Co Ltd G protein-coupled receptor inhibitor and pharmaceutical product
MX2009013354A (en) 2007-06-04 2010-07-06 Univ Ben Gurion Tri-aryl compounds and compositions comprising the same.
WO2010014836A2 (en) 2008-07-30 2010-02-04 Intercept Pharmaceuticals, Inc. Tgr5 modulators and methods of use thereof
CN102325784B (en) 2008-11-19 2014-11-19 英特塞普特医药品公司 TGR5 modulators and method of use thereof
KR101767273B1 (en) 2009-03-11 2017-08-10 오메로스 코포레이션 Compositions and methods for prophylaxis and treatment of addictions
US8581001B2 (en) 2010-04-16 2013-11-12 Codman & Shurtleff Metformin-cysteine prodrug
US20130156720A1 (en) 2010-08-27 2013-06-20 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
US20120094959A1 (en) 2010-10-19 2012-04-19 Bonnie Blazer-Yost Treatment of cystic diseases
DK3336097T3 (en) 2012-06-19 2020-09-28 Intercept Pharmaceuticals Inc Preparation of non-crystalline obeticholic acid
UA117809C2 (en) * 2012-06-19 2018-10-10 Хельмут Шикканедер BENDAMOUSTINE DERIVATIVES, RELATED COMPOUNDS AND THEIR MEDICAL APPLICATION FOR CANCER TREATMENT
US9982008B2 (en) 2012-06-19 2018-05-29 Intercept Pharmaceuticals, Inc. Preparation and uses of obeticholic acid
WO2014184104A1 (en) * 2013-05-17 2014-11-20 Boehringer Ingelheim International Gmbh Pyrrolidine derivatives, pharmaceutical compositions and uses thereof
US10111880B2 (en) 2013-11-05 2018-10-30 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
US10034868B2 (en) 2014-11-04 2018-07-31 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the prevention and the treatment of rapidly progressive glomerulonephritis
WO2016100162A2 (en) * 2014-12-19 2016-06-23 Merck Sharp & Dohme Corp. 5,5-bicyclic oxazole orexin receptor antagonists
CN104744282A (en) * 2015-02-17 2015-07-01 南通恒盛精细化工有限公司 Preparation process of insulin sensitizer
WO2019224393A1 (en) * 2018-05-25 2019-11-28 University Of Copenhagen Fenofibrate for reducing hypoglycemia in type 1 diabetes/lada

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5522636A (en) 1978-08-04 1980-02-18 Takeda Chem Ind Ltd Thiazoliding derivative
US4367234A (en) 1980-07-28 1983-01-04 Pfizer Inc. Hypoglycemic 5-substituted oxazolidine-2,4-diones
US4342771A (en) 1981-01-02 1982-08-03 Pfizer Inc. Hypoglycemic 5-substituted oxazolidine-2,4-diones
RU1473300C (en) 1987-06-01 1995-02-09 Научно-производственное объединение "Витамины" Method of synthesis of 4-benzoylamino-3-oxotetrahydrothiophene
US5220023A (en) 1989-07-18 1993-06-15 Janssen Pharmaceutica N.V. Glycine derivatives
DE3941438A1 (en) 1989-12-15 1991-06-20 Hoechst Ag NEW 2-SUBSTITUTED 4- (3-ALKYL-5-TERT.-BUTYL-4-HYDROXY-PHENYL) -THIAZOLE, PROCESS FOR THEIR MANUFACTURE, THE MEDICAMENT CONTAINING THEIR AND ITS USE
US5089514A (en) 1990-06-14 1992-02-18 Pfizer Inc. 3-coxazolyl [phenyl, chromanyl or benzofuranyl]-2-hydroxypropionic acid derivatives and analogs as hypoglycemic agents
AU3959193A (en) 1992-04-10 1993-11-18 Smithkline Beecham Plc Heterocyclic compounds and their use in the treatment of type II-diabetes
PL176885B1 (en) 1992-07-03 1999-08-31 Smithkline Beecham Plc Pharmaceutic composition
US5232945A (en) * 1992-07-20 1993-08-03 Pfizer Inc. 3-aryl-2-hydroxypropionic acid derivatives and analogs as antihypertensives
GB9225386D0 (en) 1992-12-04 1993-01-27 Smithkline Beecham Plc Novel compounds
GB9311661D0 (en) * 1993-06-05 1993-07-21 Smithkline Beecham Plc Novel compounds
GB9311644D0 (en) 1993-06-05 1993-07-21 Smithkline Beecham Plc Novel compounds
SE9302332D0 (en) 1993-07-06 1993-07-06 Ab Astra NEW COMPOUNDS
GB9315148D0 (en) 1993-07-22 1993-09-08 Smithkline Beecham Plc Novel compounds
JPH08325263A (en) * 1995-05-31 1996-12-10 Sumitomo Metal Ind Ltd New 2-amino-3-phenylpropionic acid derivative
JPH08325264A (en) * 1995-05-31 1996-12-10 Sumitomo Metal Ind Ltd New 2-aromatic ring-substituted-3-phenylpropionic acid or acrylic acid derivative
JPH08325564A (en) 1995-06-05 1996-12-10 Nec Corp Organic thin film el device
IL121202A (en) * 1996-07-01 2001-08-26 Lilly Co Eli Hypoglycemic and hypolipidemic compounds, process for their preparation, pharmaceutial compositions comprising same, and uses thereof

Also Published As

Publication number Publication date
IL125796A (en) 2001-06-14
HUP0004845A2 (en) 2001-05-28
KR19990087321A (en) 1999-12-27
MY119425A (en) 2005-05-31
YU36998A (en) 1999-09-27
BG102792A (en) 1999-08-31
AU2093597A (en) 1997-09-16
CN1218460A (en) 1999-06-02
ATE205485T1 (en) 2001-09-15
PL191118B1 (en) 2006-03-31
EP0888317A1 (en) 1999-01-07
UA58502C2 (en) 2003-08-15
HK1015369A1 (en) 1999-10-15
AP9700935A0 (en) 1997-04-30
ID15985A (en) 1997-08-21
GEP20012580B (en) 2001-11-26
RS49586B (en) 2007-04-10
US6294580B1 (en) 2001-09-25
PE43098A1 (en) 1998-08-30
HRP970110A2 (en) 1998-04-30
BR9707786B1 (en) 2009-12-01
CA2247443A1 (en) 1997-09-04
WO1997031907A1 (en) 1997-09-04
AP780A (en) 1999-11-22
EP0888317B1 (en) 2001-09-12
CY2319B1 (en) 2003-11-14
IL125796A0 (en) 1999-04-11
SI0888317T1 (en) 2002-04-30
IS1869B (en) 2003-05-09
BR9707786A (en) 1999-07-27
PL328871A1 (en) 1999-03-01
EA199800664A1 (en) 1999-04-29
GB9604242D0 (en) 1996-05-01
HUP0004845A3 (en) 2001-07-30
DK0888317T3 (en) 2002-01-21
CZ295383B6 (en) 2005-07-13
IS4822A (en) 1998-08-12
ES2163125T3 (en) 2002-01-16
CN1093124C (en) 2002-10-23
PT888317E (en) 2002-03-28
JP3255930B2 (en) 2002-02-12
JP2000507216A (en) 2000-06-13
ZA971645B (en) 1997-12-10
KR100462730B1 (en) 2005-02-28
NO983940D0 (en) 1998-08-27
SK116398A3 (en) 1999-04-13
EA001403B1 (en) 2001-02-26
AU717699B2 (en) 2000-03-30
CA2247443C (en) 2009-01-27
DE69706658D1 (en) 2001-10-18
HRP970110B1 (en) 2003-06-30
OA10843A (en) 2001-08-14
TR199801707T2 (en) 1998-12-21
SK282753B6 (en) 2002-12-03
DE69706658T2 (en) 2002-06-20
AR011502A1 (en) 2000-08-30
CZ275098A3 (en) 1999-01-13
EE9800288A (en) 1999-02-15
NO311516B1 (en) 2001-12-03
NO983940L (en) 1998-10-27

Similar Documents

Publication Publication Date Title
NZ331381A (en) Substituted 4-hydroxy-phenylalcanoic acid derivatives
AU712057B2 (en) Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity
AU728812B2 (en) Thiazole benzenesulfonamides as beta3 agonists for the treatment of diabetes and obesity
US6518290B1 (en) Substituted oxazoles and thiazoles derivatives as HPPAr alpha activators
JP4658073B2 (en) Guanidine compounds and their use as binding partners to 5-HT5 receptors
DE60216094T2 (en) MODULATORS OF PEROXISOM PROLIFERATOR ACTIVATED RECEPTORS (PPAR)
JP4345230B2 (en) Carboxylic acid derivatives and drugs containing the derivatives as active ingredients
KR20010085340A (en) Substituted Oxazoles and Thiazoles Derivatives as hPPAR Gamma and hPPAR Alpha Activators
AU2458499A (en) Inhibitors of alpha4 mediated cell adhesion
RU2296759C2 (en) N-substituted 1h-indole-5-propionic acids, pharmaceutical composition containing these compounds and their using (variants)
JP2007510629A (en) Novel MCH receptor antagonist
US7241784B2 (en) Carboxylic acid derivative and a pharmaceutical composition containing the derivative as active ingredient
US20120015957A1 (en) Piperazinyl derivatives useful as modulators of the neuropeptide y2 receptor
KR20130099077A (en) Bace inhibitors for use in the treatment of diabetes
KR100621294B1 (en) Oxazole derivatives and their use as insulin sensitizers
MXPA01001419A (en) SUBSTITUTED OXAZOLES AND THIAZOLES DERIVATIVES AS hPPAR GAMMA AND hPPAR ALPHA ACTIVATORS

Legal Events

Date Code Title Description
RENW Renewal (renewal fees accepted)
RENW Renewal (renewal fees accepted)
RENW Renewal (renewal fees accepted)
EXPY Patent expired